Disorders of Esophageal Motility

Robert J. Washabau, VMD, PhD, Dipl. ACVIM
Professor of Medicine and Department Chair
Department of Veterinary Clinical Sciences
College of Veterinary Medicine; University of Minnesota
1352 Boyd Avenue, St. Paul, Minnesota 55108
(612) 625-5273; (612) 624-0751
washabau@umn.edu

ESOPHAGEAL DYSMOTILITY

Esophageal dysmotility is a primary motility disorder of the esophagus characterized by reduced esophageal peristalsis, food retention, and regurgitation. It is not necessarily accompanied by esophageal dilation or permanent megaesophagus, and therefore is not referred to as idiopathic megaesophagus. Esophageal dysmotility has been reported in young dogs as a consequence of delayed maturation,1-7 muscular dystrophy,8-9 myasthenia gravis,10 inflammatory myopathy,11,12 transient dysfunction following anesthetic episodes,13 and breed-specific abnormalities.14

Therapy is primarily supportive and follows therapy outlined for idiopathic megaesophagus (see Box 56.1). The prognosis for esophageal dysmotility is generally more favorable than it is for idiopathic megaesophagus.

IDIOPATHIC MEGAESOPHAGUS

Etiology
The term idiopathic megaesophagus refers to concurrent esophageal dysmotility and dilation of unknown etiology, and is the most common cause of regurgitation in the dog.15,16 Aside from dysautonomia, megaesophagus is an uncommon finding in the cat. The canine disorder is characterized by progressive regurgitation, aspiration pneumonia and loss of body condition. Several forms of the syndrome have been described, including congenital, acquired secondary, and acquired idiopathic megaesophagus.16

Pathophysiology
Congenital idiopathic megaesophagus is a generalized hypomotility and dilation of the esophagus causing regurgitation and failure to thrive in puppies shortly after weaning. An increased breed incidence has been reported in the German shepherd, Great Dane, Irish setter, Labrador retriever, Chinese Shar-Pei, and Newfoundland breeds, and autosomal dominant inheritance has been demonstrated in the Miniature Schnauzer and Fox terrier breeds.16 The pathogenesis of the congenital form is incompletely understood, although several studies have pointed to a defect in the vagal afferent innervation of the esophagus.2-6,17 Primary, but not secondary, esophageal peristalsis appears to be intact in this disorder. Congenital idiopathic megaesophagus has been reported in several cats18 and in one group of cats secondary to pyloric dysfunction.19

Acquired secondary megaesophagus may develop in association with a number of other conditions. Myasthenia gravis accounts for 25-30% of the secondary cases.10,20,21 In some cases of myasthenia gravis, regurgitation and weight loss may be the only presenting signs of the disease, whereas in most other cases of acquired secondary megaesophagus regurgitation is but one of many clinical signs including peripheral muscle weakness. Acquired secondary megaesophagus has also been associated with hypoadrenocorticism, lead poisoning, lupus myositis, and severe forms of esophagitis.16 Hypothyroidism has been suggested as a secondary cause of idiopathic megaesophagus but retrospective risk factor analysis has not identified it as an important cause.15

Acquired-idiopathic megaesophagus usually has no known underlying etiology and occurs spontaneously in adult dogs between 7 to 15 years of age with no sex or breed predilection. The disorder has been compared erroneously to gastroesophageal achalasia in humans. Achalasia is a hypertensive sphincteric disorder characterized by failure of relaxation of the lower esophageal sphincter and ineffective peristalsis of the esophageal body.1 A similar disorder has never been rigorously documented in the dog although putative case reports are occasionally reported.22 Several important differences between idiopathic megaesophagus in the dog and achalasia in humans have been documented.1,2,17 Although the precise etiology has not yet been identified, some studies have suggested a defect in the afferent neural response to esophageal distension similar to what has been reported in congenital megaesophagus .23

Clinical Examination
Regurgitation is the most frequent clinical sign associated with megaesophagus. The frequency of regurgitation varies from intermittent irregular episodes to multiple episodes per day. As with other esophageal disorders, affected animals suffer from malnutrition and aspiration pneumonia. Physical examination may reveal excessive salivation, mild to moderate cachexia, coughing, and pulmonary crackles or wheezes.

Diagnosis
Routine hematology, serum biochemistry, and urinalysis should be performed in all cases to investigate possible secondary causes of megaesophagus. Survey radiographs will be diagnostic for most cases of megaesophagus, but generally do not differentiate one cause versus another.24 Contrast radiographs may be necessary in some cases to confirm the diagnosis, evaluate motility, and exclude foreign bodies or obstruction as the cause of the megaesophagus. Endoscopy will confirm the diagnosis and may further reveal esophagitis, a frequent finding in canine idiopathic megaesophagus.15,16 Risk factor analysis suggests that esophagitis markedly increases the risk for the development of megaesophagus.15,16 Esophagitis could be cause or consequence of esophageal dysmotility and megaesophagus.

If acquired secondary megaesophagus is suspected, additional diagnostic tests should be considered, including serology for nicotinic acetylcholine receptor antibody, pre and post-ACTH [cortisol], serum creatine phosphokinase activity, electromyography and nerve conduction velocity, and muscle and nerve biopsy.16 Additional medical investigation will be dependent upon the individual case presentation. Hypothyroidism has been cited as an important cause of idiopathic megaesophagus in the dog, although risk factor analysis has not revealed a clear association.15 Thyroid function testing (e.g., TSH assay, TSH stimulation, free and total thyroid hormones) should be performed only in individual suspected cases.

Treatment (Box 56.1)
Animals with secondary acquired megaesophagus should be appropriately differentiated from other esophageal disorders (Table 56.1). Dogs affected with myasthenia gravis should be treated with pyridostigmine (1.0-3.0 mg/kg p/o bid), corticosteroids (prednisone 1.0-2.0 mg/kg p/o or s/c bid), or azathioprine (2 mg/kg p/o sid initially, 0.5-1.0 mg/kg p/o every other day). Mycophenolate has been recommended in the treatment of myasthenia gravis, but a recent report suggests that mycophenolate does not improve outcome over pyridostigmine alone.25 Dogs affected with hypothyroidism should be treated with levothyroxine (22 µg/kg p/o bid), and dogs affected with polymyositis should be treated with prednisone (1.0-2.0 mg/kg p/o bid). If secondary disease can be excluded, therapy for the congenital or acquired idiopathic megaesophagus patient should be directed at nutritional management and treatment of aspiration pneumonia.

Affected animals should be fed a high-calorie diet, in small frequent feedings, from an elevated or upright position to take advantage of gravity drainage through a hypomotile esophagus. Dietary consistency should be formulated to produce the fewest clinical signs. Some animals handle liquid diets quite well, while others do better with solid meals. Animals that cannot maintain adequate nutritional balance with oral intake should be fed by temporary or permanent tube gastrostomy. Gastrostomy tubes can be placed surgically or percutaneously with endoscopic guidance.

Pulmonary infections should be identified by culture and sensitivity, and an appropriate antibiotic selected for the offending organism(s). This may be accomplished by trans- or endo-tracheal wash or by bronchoalveolar lavage at the time of endoscopy.

Smooth muscle prokinetic (e.g., metoclopramide or cisapride) therapy has been advocated for stimulating oesophageal peristalsis in affected animals, however metoclopramide and cisapride will not have much of an effect on the striated muscle of the canine esophageal body.26,27,28 Esophageal 5-HT4 receptors are present in many animal species, but are apparently absent in canine esophageal striated muscle.26 Bethanechol (5-15 mg/dog p/o tid) has been shown to stimulate esophageal propagating contractions in some affected dogs and is therefore a more appropriate prokinetic agent for the therapy of this disorder.17 Because of the high incidence of esophagitis in canine idiopathic megaesophagus,15 affected animals should also be medicated with oral sucralfate suspensions (1 g tid for large dogs, 0.5 g tid for smaller dogs, and 0.25 to 0.5 g bid-tid for cats).

Surgical cardiomyotomy (myotomy of the gastroesophageal sphincter) has been recommended in the past as a therapeutic measure in the belief that canine megaesophagus is similar to human achalasia. Because most studies have reported normal gastroesophageal sphincter tone and appropriate relaxation with swallowing,23 cardiomyotomy cannot be recommended for the treatment of this disorder. Indeed, animals treated with myotomy generally have had poorer outcomes than untreated animals.

Prognosis
Animals with congenital idiopathic megaesophagus have a fair prognosis. With adequate attention to caloric needs and recognition of episodes of aspiration pneumonia, many animals will develop improved esophageal motility over several months. Pet owners must be committed to months of physical therapy and nutritional support.

The morbidity and mortality of acquired idiopathic megaesophagus remain unacceptably high. Many animals eventually succumb to the effects of chronic malnutrition and repeated episodes of aspiration pneumonia. A poor prognosis must be given in such cases.

Animals with acquired secondary megaesophagus have a more favorable prognosis if the underlying disease can be promptly identified and successfully managed. Refractory cases result from chronic esophageal distension, myenteric nerve degeneration, and muscle atrophy

DYSAUTONOMIA

Etiology
Dysautonomia is a generalized autonomic neuropathy that was originally reported in cats in the United Kingdom, but that has now been documented in dogs and cats throughout Western Europe and the United States.29-35 The clinical signs reflect a generalized autonomic dysfunction but megaesophagus, esophageal hypomotility, and regurgitation are fairly consistent findings.29,31

Pathophysiology
Degenerative lesions are found in autonomic ganglia, intermediate gray columns of the spinal cord, and some sympathetic axons.31,33,34 Despite an intensive search for genetic, toxic, nutritional, and infectious etiologic agents, no definitive etiology has ever been established.

Clinical Signs
The most frequently reported clinical signs are depression, anorexia, constipation, and regurgitation or vomiting. Fecal and urinary incontinence have been reported less commonly. Physical examination findings consistent with dysautonomia include dry mucous membranes, pupillary dilation, prolapsed nictitating membranes, reduced or absent pupillary light reflex, bradycardia, and areflexic anus. Paresis and conscious proprioceptive deficits have been reported in a small number of cases.33

Diagnosis
A clinical diagnosis is made in most cases based on historical and physical examination findings. Additional findings consistent with the diagnosis would include: 1) esophageal dilation and hypomotility on survey or barium contrast radiographs; 2) delayed gastric emptying on barium contrast radiographs; 3) reduced tear production in Schirmer tear tests; 4) atropine-insensitive bradycardia; and, 5) bladder and colonic distention on survey radiographs. There are few differential diagnoses to consider in a dog or cat presenting with the myriad manifestations of the syndrome. Early in the course of the illness, however, other differential diagnoses to consider are colonic or intestinal obstruction, other causes of megaesophagus, and lower urinary tract disease.

Treatment
Supportive care (e.g. artificial tears, elevated feedings, expressing the urinary bladder, antibiotics, etc.) is still the basis of therapy in this disorder, although some dogs and cats are reported to show mild improvement with parasympathomimetic drugs (e.g. bethanechol or metoclopramide). Gastrostomy tube feedings or total parenteral nutrition may sustain some animals until they regain neurologic function.

Prognosis
In general, dysautonomia carries a guarded to poor prognosis for long-term survival in both the dog and the cat. 20 to 40% of affected cats are likely to recover, although cats may take 2 to 12 months to do so.33-35 Recovery rates are lower still in the dog.31,33 Complete recovery is uncommon and many cats and dogs are left with residual impairment, e.g. intermittent regurgitation, dilated pupils, and fecal or urinary incontinence.

ESOPHAGEAL DIVERTICULA

Etiology
Esophageal diverticula are circumscribed sacculations in the wall of the esophagus that interfere with the normal esophageal motility patterns. Both congenital and acquired forms have been described.36

Pathophysiology
Congenital diverticula have been attributed to abnormalities in embryologic development that permit herniation of the mucosa through a defect in the muscularis. Acquired diverticula are subdivided into either traction or pulsion forms, depending upon the pathogenesis. Traction diverticula tend to develop in the cranial and mid-esophageal body and result from peri-esophageal inflammation and fibrosis. Adhesions to adjacent tissue (e.g. lung, bronchus, lymph node) distort the esophageal lumen and create sacculations. Abscess development from grass awn migration is a common cause of traction diverticula in the western United States. Pulsion diverticula develop in association with increases in intraluminal esophageal pressure, abnormal regional esophageal motility, or when normal peristalsis is obstructed by a stenotic lesion.16 Pulsion diverticula may develop as a consequence of vascular ring anomalies in the cranial esophagus, or from foreign bodies that become lodged in the distal esophagus, in which case they are referred to as epiphrenic diverticula.

Clinical Signs
The clinical signs of esophageal diverticula are typical of many other esophageal disorders, and include regurgitation, odynophagia (painful swallowing), and retching. Signs usually result from impaction of food and/or fluid in the sacculated segment. On rare occasions, weakening of the muscularis results in perforation of the diverticulum, leakage of food and fluid into the mediastinum, and signs of sepsis.

Diagnosis
Survey radiographs may reveal an air-filled or tissue-density mass adjacent to or involving the esophagus. Contrast radiographs are necessary, however, because it may be impossible to differentiate an esophageal diverticulum from a peri-esophageal, mediastinal, or pulmonary mass. An epiphrenic diverticulum could also easily be confused with a hiatal hernia or gastroesophageal intussusception on survey radiographs. Contrast radiographs will demonstrate a focal dilated segment of esophageal lumen that fills partially or completely with contrast media. Videofluoroscopy might also demonstrate an underlying esophageal motility disorder associated with the diverticulum. Endoscopy will confirm the diagnosis, although it may be necessary to suction food and fluid to visualize the diverticulum. The differential diagnoses for cranial and mid-esophageal diverticula should include esophageal or peri-esophageal abscess, necrotic tumour, and pulmonary mass. Hiatal hernia and gastroesophageal intussusception are the major differential diagnoses for epiphrenic diverticula. The normal redundancy of the canine esophagus frequently seen in the brachycephalic breeds should not be confused with the sacculation of an esophageal diverticulum.

Treatment
Small diverticula may be managed by feeding liquid or semiliquid diets to minimize impaction of solid food in the diverticulum. Surgical excision and reconstruction of the esophageal wall are required for larger diverticulae. Even small pulsion diverticula should probably be treated surgically since food impaction might cause them to enlarge.

Prognosis
Most cases warrant a guarded prognosis since segmental esophageal hypomotility may persist after surgery. Animals are also at some risk for esophageal stricture following corrective surgery. In cases of traction diverticula, the prognosis will also be somewhat dependent upon the pathogenesis and resolution of the peri-esophageal inflammation.

REFERENCES

1. Diamant N, Szczepanski M, and Mui H. Manometric characteristics of idiopathic megaesophagus in the dog: An unsuitable model for achalasia in man. Gastroenterology 65: 216-223, 1973
2. Tan BJK and Diamant N. Assessment of the neural defect in a dog with idiopathic megaesophagus. Dig Dis Sci 32: 76-85, 1987.
3. Holland CT, Satchell PM, and Farrow BRH. Oesophageal compliance in naturally occurring canine megaoesophagus. Aus Vet J 70: 414-420, 1993
4. Holland CT, Satchell PM, and Farrow BRH. Vagal afferent dysfunction in naturally occurring canine esophageal motility disorder. Dig Dis Sci 39: 2090-2098, 1994.
5. Holland CT, Satchell PM, and Farrow BRH. Vagal esophagomotor nerve function and esophageal motor performance in dogs with congenital idiopathic megaesophagus. Am J Vet Res 57: 906-911, 1996.
6. Holland CT, Satchell PM, and Farrow BRH. Selective vagal afferent dysfunction in dogs with congenital idiopathic megaoesophagus. Autonomic Neuroscience: Basic & Clinical 99: 18-23, 2002.
7. Bexfield NH, Watson PJ, and Herrtage ME. Esophageal dysmotility in young dogs. J Vet Intern Med 20: 1314-1318, 2006.
8. Peeters ME, Venker-van Haagen AJ, Goedegebuure SA, et al. Dysphagia in Bouviers associated with muscular dystrophy: evaluation of 24 cases. Vet Quart 13: 65-73, 1991.
9. Peeters ME and UbbinkGJ. Dysphagia-associated muscular dystrophy: a familial trait in the Bouvier des Flandres. Vet Rec 134: 444-446, 1994.
10. Dickinson PJ, Sturges BK, Shelton GD, et al. Congenital myasthenia gravis in smooth-haired miniature dachshund dogs. J Vet Intern Med 19: 920-923, 2005.
11. Evans J, Levesque D, and Shelton GD. Canine inflammatory myopathies: a clinicopathologic review of 200 cases. J Vet Intern Med 18: 679-691, 2004.
12. Mazzei MJ, Bissett SA, Murphy KM, et al. Eosinophilic esophagitis in a dog. J Am Vet Med Assoc 235; 61-65, 2009.
13. Hendricks JC, Maggio-Price L, Dougherty JF. Transient esophageal dysfunction mimicking megaesophagus in three dogs. J Am Vet Med Assoc 185; 90-92, 1984.
14. Stickle R, Sparschu G, Love N, et al. Radiographic evaluation of esophageal function in Chinese Shar pei pups. J Am Vet Med Assoc 201; 81-84, 1992.
15. Gaynor A, Shofer F, and Washabau RJ. Risk factors associated with the development of canine acquired megaesophagus. J Am Vet Med Assoc 211: 1406-1412, 1997.
16. Washabau RJ. Diseases of the Esophagus. In: Textbook of Veterinary Internal Medicine. 5th edition. Eds. SJ Ettinger and EC Feldman, WB Saunders Company, Philadelphia, pp 1142-1153, 2000.
17. Diamant N, Szcepanski M, and Mui H. Idiopathic megaesophagus in the dog: Reasons for spontaneous improvement and a possible method of medical therapy. Can Vet J 15: 66-71, 1074.
18. Hoenig M, Mahaffey MB, Parnell PG, et al. Megaesophagus in two cats. J Am Vet Med Assoc 196: 763-765, 1990.
19. Pearson H, Gaskell CJ, Gibbs C, et al. Pyloric and oesophageal dysfunction in the cat. J Small Anim Pract 15: 487-501, 1974.
20. Shelton GD, Willard MD, Cardinet GH, et al. Acquired myasthenia gravis: selective involvement of esophageal, pharyngeal, and facial muscles. J Vet Intern Med 4: 281-284, 1990.
21. Shelton GD, Schule A, and Kass PH. Risk factors for acquired myasthenia gravis in dogs. J Ame Vet Med Assoc 211: 1428-1431, 1997.
22. Boria PA, Webster CRL, and Berg J. Esophageal achalasia and secondary megaesophagus in a dog. Can Vet J 44: 232-234, 2003
23. Washabau RJ. Canine megaesophagus: pathogenesis and therapy. Proceedings of the American College of Veterinary Internal Medicine Forum 10: 671-673, 1992.
24. Wray JD and Sparkes AH. Use of radiographic measurements in distinguishing myasthenia gravis from other causes of canine megaesophagus. JSAP 47: 256-263, 2006.
25. Dewey CW, Cerda-Gonzalez S, Fletcher DJ, et al. Mycophenolate mofetil treatment in dogs with serologically diagnosed acquired myasthenia gravis. J Am Vet Med Assoc 236; 664-668, 2010.
26. Cohen ML, Susemichel AD, and Bloomquist W. 5-HT4 receptors in rat but not rabbit, guinea pig, or dog esophageal muscle. Gen Pharm 25: 1143-1148, 1994.
27. Hall JA, Washabau RJ. Gastrointestinal prokinetic therapy: dopaminergic antagonist drugs. Compendium Contin Educ Pract Vet 19: 214-221, 1997
28. Washabau RJ, Hall JA. Gastrointestinal prokinetic therapy: serotonergic drugs. Compendium of Contin Educ Pract Vet 19: 473-480, 1997.
29. Berghaus RD, O’Brien DP, Johnson GC, et al. Risk factors for development of dysautonomia in dogs. J Am Vet Med Assoc 218: 1285-1290, 2001
30. Detweiler DA, Biller DS, Hoskinson JJ, et al. Radiographic findings of canine dysautonomia in twenty-four dogs. Vet Radiol & Ultrasound 42: 108-112, 2001.
31. Harkin KR, and Andrews GA, and Nietfeld JC. Dysautonomia in dogs: 65 cases (1993-2000). J Am Vet Med Assoc 220: 633-639, 2002.
32. Harkin KR, Nietfeld J, and Fischer JR. Dysautonomia in a family of German shorthaired pointers. JAAHA 38: 55-59, 2002.
33. O’Brien DP and Johnson GC. Dysautonomia and autonomic neuropathies. Vet Clin N Amer – Small Anim Pract. 32: 251-265, 2002.
34. Sharp NJH. Feline dysautonomia. Semin Vet Med Surg 5: 67-71, 1990.
35. Kidder AC, Johannes C, O’Brien DP, et al. Feline dysautonomia in the Midwestern United States: a retrospective study of nine cases. J Fel Med Surg 10: 130-136, 2007.
36. Pearson H, Gibbs C, and Kelly DF . Oesophageal diverticulum formation in the dog. J Small Anim Pract 19, 341-355, 1978.

Box 56.1 – Therapy for canine idiopathic megaesophagus.
Problem Therapy
Regurgitation of food Elevated feedings, liquid to semi-liquid density
Malnutrition High biological, high energy feedings
Pulmonary infections Broad spectrum antibiotics
Esophageal dysmotility Bethanechol
Esophagitis Oral Sucralfate (liquid suspension)

Table 56.1. Medical investigation and treatment of canine idiopathic megaesophagus.

ETIOLOGY MEDICAL INVESTIGATION TREATMENT
Congenital Megaesophagus
Myasthenia gravis Edrophonuim response ± electrophysiology Pyridostigmine (1.0-3.0 mg/kg p/o, bid)
Neuropathy Esophageal manometry ± electrophysiology Elevated, small frequent feedings; bethanechol (5-15 mg/dog p/o tid)
Acquired Idiopathic Megaesophagus
Neuropathy Esophageal manometry ± electrophysiology Elevated, small frequent feedings, bethanechol (5-15 mgdog p/o tid),
sucralfate (0.5-1.0 grams p/o, tid), antibiotics as needed
Acquired Secondary Megaesophagus
Myasthenia gravis Nicotinic acetylcholine receptor antibody, Pyridostigmine (1.0-3.0 mg/kg p/o, bid)
edrophonium response, ± electrophysiology ± prednisone (1.0-2.0 mg/kg p/o or s/q, bid)
Hypoadrenocorticism ACTH stimulation Prednisone (0.1 mg/kg p/o, bid),
Lead toxicity Hematology, blood lead concentrations Chelation with calcium EDTA
Esophagitis Esophageal endoscopy Sucralfate (0.5-1.0 grams p/o, tid), cimetidine (5-10 mg/kg p/o, tid), omeprazole (0.7 mg/kg p/o, sid)
Hypothyroidism Thyroid function tests Levothyroxine (22 μg/kg p/o, bid)
Dysautonomia Clinical diagnosis Supportive care
Polymyositis/polymyopathy Serum creatine phosphokinase, muscle Prednisone (1.0-2.0 mg/kg p/o or s/q, bid)
biopsy ± electrophysiology
Systemic lupus erythematosus Anti-nuclear antibody Prednisone (1.0-2.0 mg/kg p/o or s/q, bid)

Figure 56.3

Inter-Relationships Between Gastroesophageal Reflux, Esophagitis, Esophageal Dysmotility, and Idiopathic Megaesophagus

Cause
Gastroesophageal Reflux → Reflux Esophagitis → Esophageal Dysmotility → Idiopathic Megaesophagus

Consequence
Esophageal Dysmotility → Idiopathic Megaesophagus → Gastroesophageal Reflux → Reflux Esophagitis

Gastric Motility Disorders

GASTRIC PHYSIOLOGY
Anatomically, the stomach is composed of five distinct anatomic components: cardia, fundus, corpus, antrum, and pylorus. Physiologically, the stomach can be thought of as a two-component model: a proximal stomach (cardia, fundus, first ⅓ of the corpus) characterized by slow tonic contractions, and a distal stomach (distal ⅔ of the corpus and antrum) characterized by phasic propagating contractions .1 Slow waves without action potentials give rise to the sustained tonic contractions of the proximal stomach. During swallowing, gastroesophaeal sphincter and intragastric pressure decrease to accommodate emptying of solids and liquids. This phenomenon, referred to as “receptive relaxation”, takes place with each swallow, and as a consequence, large volumes can be accommodated with minimal increases in intragastric pressure. The proximal stomach becomes much less compliant with fundic disease or fundectomy.

A pacemaker site in the proximal fundus of the greater curvature generates action potentials and phasic contractions that propagate from the site of origin circumferentially and distally to the pylorus.2 During feeding, phasic contractions of the distal stomach trigger a repetitive cycle of propulsion, trituration, and retropulsion that progressively reduce the size of the ingesta. Thus, the peristaltic qualities of the distal stomach regulate the emptying of solid particles into the duodenum. Antral disease or antrectomy abolish this physiologic effect resulting in a “dumping syndrome” due to accelerated gastric emptying, nutrient overload in the small intestine, and an osmotic type diarrhea.

Gastric emptying is regulated by several physiologic parameters, including: (1) pyloric resistance and pressure differential between the stomach and duodenum; (2) water content – liquids are emptied more rapidly than solids; (3) nutrient composition – carbohydrates are emptied more rapidly than proteins which in turn are more emptied more rapidly than lipids; (4) nutrient acidity – delayed at acid or alkaline pH; (5) nutrient osmolality – delayed at high osmolality; and, (6) hot or cold temperatures. Duodenal, jejunal, and ileal braking mechanisms also feedback inhibit gastric emptying through activation of mucosal sensory receptors for fatty acids, tryptophan, osmolality, and acid. Intestinal braking mechanisms serve to prolong transit time and nutrient contact time.1

During the fasting state the stomach is ordinarily empty, aside from swallowed saliva, a small amount of mucus, and cellular debris that collects in the gastric lumen. In addition, there may be particles of indigestible solids left over from the previous meal. A special mechanism exists to empty this fasting content called the migrating motility complex (MMC). The ability of the MMC to completely empty the stomach of its residue is so striking that it is sometimes referred to as the “interdigestive housekeeper” of the gastrointestinal tract.1 The gastrointestinal hormone, motilin, is involved in the regulation of this MMC pattern. Cats and rabbits do not have a migrating motility complex, and instead have a less vigorous emptying pattern known as the migrating spike complex (MSC).3,4

CLINICAL SIGNS OF DISEASE

Delayed gastric emptying most often results in the clinical signs of gastric distension, retention of food, and vomiting (see Table 56-1). A gastric motility disorder should be considered when there is a history of chronic vomiting. Vomiting may or may not be associated with feeding. Typically, vomiting of undigested or partially digested food is observed 8 to 10 hours after feeding, at a time when the stomach should be empty of ingested solids. The character of the vomitus is dependent on time lapse since the last meal, degree of gastric trituration, amount of gastric secretions, and extent of hydrolytic digestion. Other signs of a gastric motility disorder may include anorexia, belching, polydipsia, pica, and weight loss. Animals may occasionally assume a position of relief referred to as the “praying posture” to relieve gastric pain. The physical examination may be normal or may reveal findings associated with the underlying disease process. Abdominal distension may be present, increased bowel sounds may be noted with abdominal auscultation, and nonspecific pain may be evoked on abdominal palpation. Palpable abdominal masses are most consistent with intestinal or other visceral neoplasia, foreign bodies, and intussusceptions. Neuromuscular abnormalities may also be observed in dogs with severe electrolyte or metabolic derangements secondary to chronic vomiting.

PATHOPHYSIOLOGY – GASTRIC OUTFLOW OBSTRUCTION

Anatomic lesions of the pylorus and adjacent duodenal segment impede gastric emptying because of mechanical obstruction.5,6 In general, diagnosis of mechanical obstruction is usually straightforward and involves survey and contrast radiography, ultrasonography, or gastroscopy. Surgical removal of the foreign object of the affected area is the preferred therapy. Gastrointestinal prokinetic agents are generally contraindicated in treating patients with mechanical obstruction.

Simple and Linear Foreign Bodies – Gastric foreign body ingestion is a common occurrence, particularly in young puppies. Many different types of foreign bodies are ingested in companion animals, from bones to cartilage, coins and other metal objects, strings/yarn, and nylons. Many of these can be managed with endoscopy, but others may require surgical removal.

Antral Pyloric Hypertrophy – Pyloric stenosis or chronic hypertrophic pyloric gastropathy is a common cause of gastric outflow obstruction.6-11 Most affected dogs are of male gender, young to middle-aged, brachycephalic, or of small breeds. Histopathologic changes include hypertrophy of the circular muscles of the pylorus, hyperplasia of the antropyloric mucosa, or a combination of both muscular hypertrophy and mucosal hyperplasia, with or without inflammation. Antral pyloric hypertrophy may occur as a congenital lesion in young animals (congenital pyloric stenosis – reported in boxer and Boston terrier breeds), or as an acquired lesion in older animals (chronic hypertrophic pyloric gastropathy – reported in Lhasa apso, Shih Tzu, Maltese, and Pekingese breeds). Positive-contrast radiographic studies are useful in documenting gastric outflow obstruction. Ultrasonography can help identify a thick hypoechoic layer of pyloric muscle and a thickened gastric wall.12 The diagnosis is confirmed by the endoscopic appearance of enlarged mucosal folds surrounding the pyloric orifice and by exclusion of other causes by mucosal biopsies.13 Surgery, for example, pyloroplasty, is the treatment of choice for both lesions.

Gastric Phycomycosis – Gastric phycomycosis is a systemic fungal disease caused by the ubiquitous fungus Pythium.14-16 This infectious disease is seen most often in the southeastern United States, but solitary cases have been seen throughout the United States. The organism elicits an intense inflammatory and fibrotic reaction often mimicking inflammatory carcinomas. Dogs may be presented for chronic debilitation and vomiting because of pyloric mechanical obstruction. An abdominal mass is often palpable on physical examination, and positive-contrast radiographic studies reveal a thickened gastric wall.17 Definitive diagnosis is made by identifying the organism with special stains in histological sections, fungal culture, serology, or PCR.18 Phycomyosis lesions are best managed by surgical resection followed by systemic anti-fungal therapy.

Chronic Gastritis – Chronic hypertrophic gastritis may be associated with diffuse or focal macroscopic thickening of the gastric mucosa, leading to progressive obstruction to outflow. Histopathologic changes include mucosal hypertrophy and hyperplasia of gastric glands, with inflammatory cells and cystic dilatation of mucous glands.18-20 Hypertrophic gastritis is probably the result of chronic mucosal inflammation. Contrast radiography is sometimes useful in demonstrating lesions, but a definitive diagnosis usually requires endoscopy and gastric biopsy. Dietary modification may be helpful in these patients.

Eosinophilic Gastritis – This lesion characterized by chronic eosinophilic infiltration of the gastric mucosa can also cause obstructive pyloric lesions. Lesions usually consist of diffuse eosinophilic infiltrates, granulation tissue, and fibrosis involving the mucosa and other layers of the gastric wall. Less frequently, discrete granulomatous nodules may be present.18-20 The etiopathogenesis is unknown, although some cases may result from an underlying parasitic or allergic reaction.18-20 Definitive diagnosis is based on gastric biopsy. Surgical correction of pyloric obstruction may be required, but dietary manipulation (hypoallergenic or elimination diet) and glucocorticoid therapy are the mainstays of therapy.

Gastric Neoplasia – Adenocarcinomas are the most common malignant gastric tumor in dogs, and metastasis is common. Lymphosarcomas are the most common gastric tumor in cats. Other primary malignant tumors include leiomyo(sarco)mas, plasmacytomas, and fibrosarcomas.22-25 Clinical signs include chronic vomiting, hematemesis, melena, anorexia, and weight loss. Endoscopy or exploratory laparotomy and biopsy are required for definitive diagnosis. The prognosis for malignant gastric neoplasia is usually poor because of the advanced nature of the lesion at the time of diagnosis and because of complications associated with gastric resection. Extrinsic pyloric lesions such as hepatic or pancreatic neoplasms can also cause gastric outflow obstruction via extramural compression of the pylorus

PATHOPHYSIOLOGY – GASTRIC MOTILITY DISORDERS
Accelerated Gastric Emptying – The best example of an accelerated gastric emptying disorder is the vomiting associated with the hyperthyroxinemia of feline hyperthyroidism. Hyperthyroxinemia induces a tachygastria and accelerated gastric emptying. Normal gastric emptying rhythm is restored following successful treatment of hyperthyroidism. Accelerated gastric emptying occasionally occurs in dogs following antral and/or pyloric resections for the treatment of gastric cancer. A post-prandial “dumping syndrome” develops in these animals characterized by acute vomiting, abdominal pain, and diarrhea.

Retrograde Transit – Gastroesophageal reflux and duodenogastric reflux are the two best examples of retrograde transit disorders. Gastroesophageal reflux is an increasingly recognized clinical disorder in the dog, although clinical signs are more related to esophageal dysfunction.21,26 Duodenogastric reflux may be the underlying pathogenesis of the so-called “bilious vomiting” syndrome in the dog. Affected animals tend to vomit small amounts of bile in the morning following an overnight fast

Delayed Gastric Emptying – Delayed gastric emptying is now recognized as an important cause of upper gastrointestinal tract signs.18-20 Delayed gastric emptying has been reported in animals recovering from gastric dilatation/volvulus (Figure 56-3), infectious and inflammatory gastric diseases, experimental gastric ulcer, and radiation gastritis. It has also been associated with several secondary conditions, including electrolyte disturbances (e.g., hypokalemia), metabolic disorders (e.g., hypoadrenocorticism, uremia, diabetes mellitus), concurrent drug usage (e.g., anti-cholinergics), and acute abdominal inflammation

GASTRIC PROKINETIC THERAPY
Dietary management should always be used as an adjunct to G.I. prokinetic therapy. Dietary management is based on the knowledge that liquids are emptied from the stomach more rapidly than solids, and that carbohydrates are emptied more rapidly than proteins, which in turn are emptied more rapidly than lipids. A low-fat, low-protein diet of liquid or semi-liquid consistency should be fed at frequent intervals to facilitate gastric emptying. Diets should be selected for low acidity and low osmolality and should be fed at warm temperatures (22 – 38 C; 72 – 100 F). Gastric prokinetic agents should be considered in patients that fail to respond to dietary management alone.

Dopaminergic Antagonistic Drugs
The dopaminergic antagonists are a group of drugs with gastrointestinal prokinetic and antiemetic effects at peripheral (prokinetic) or central (antiemetic) dopamine D2 receptors. The best representatives in this classification, metoclopramide and domperidone, reverse gastric relaxation induced by dopamine infusion in dogs, and they abolish vomiting associated with apomorphine therapy. Although the role of dopamine receptors in chemoreceptor trigger zone-induced vomiting is fairly well established, there is no definitive evidence that inhibitory dopaminergic neurons regulate gastrointestinal motility. The prokinetic effects of metoclopramide and domperidone thus may not be readily or exclusively explained by dopamine receptor antagonism. Some dopaminergic antagonists (e.g., metoclopramide) have other pharmacologic properties, e.g., 5-HT3 receptor antagonism and 5-HT4 receptor agonism. Domperidone also has 2- and 2-adrenergic receptor antagonistic effects. The characterization of these drugs as dopaminergic antagonists is convenient but may not properly describe their overall in vivo effects.

Serotonergic Drugs
Drugs acting on gastrointestinal 5-hydroxytryptamine (5-HT or serotonin) receptors have potent motility effects. As prokinetic agents, the serotonergic drugs bind 5-HT4 receptors on enteric cholinergic neurons inducing depolarization and contraction of gastrointestinal smooth muscle. These drugs are not entirely selective for the 5-HT4 receptor, however. Some of the putative 5-HT4 receptor agonists also have 5-HT1 and 5-HT3 antagonistic effects on enteric cholinergic neurons, and direct non-cholinergic (perhaps 5-HT2a) effects on colonic smooth muscle. Cisapride and tegaserod were perhaps the best examples in this classification although it has been withdrawn from several markets, including the United States, Canada, and several western European countries.

Motilin-Like Drugs
The antibiotic properties of erythromycin and other macrolides were discovered in the early 1950’s. Since that time, erythromycin has been widely used in treating patients with gram-positive and gram-negative bacterial and mycoplasmal infections. Physicians and veterinarians noted that erythromycin therapy was accompanied by frequent gastrointestinal side effects including nausea and vomiting. This occurrence suggested to researchers that erythromycin might have effects on gastrointestinal motility. It was subsequently demonstrated that microbially-effective doses of erythromycin stimulate retrograde peristalsis and vomiting in dogs, and that lower microbially-ineffective doses of erythromycin stimulate migrating motility complexes and antegrade peristalsis similar to that induced by the endogenous gastrointestinal hormone, motilin.

Acetylcholinesterase Inhibitors and Cholinomimetic Agents
Ranitidine and nizatidine, classic histamine H2 receptor antagonists, stimulate gastrointestinal motility by inhibiting acetylcholinesterase activity. As parasympathetic potentiating agents, ranitidine and nizatidine stimulate gastric emptying and small intestinal and colonic motility. The prokinetic effects of ranitidine and nizatidine appear to be more prominent in the proximal gastrointestinal tract (i.e., gastric emptying). Other members of this classification, e.g., cimetidine and famotidine, apparently have no effect on gastrointestinal motility. Bethanechol is a cholinomimetic agent that binds muscarinic cholinergic receptors and stimulates motility throughout the gastrointestinal tract.

NITRIC OXIDE DONORS
Delayed gastric emptying is recognized as an important cause of upper gastrointestinal tract pathology (e.g., anorexia and vomiting) in companion animals.21 Delayed gastric emptying has been reported in infectious and inflammatory gastric diseases, diabetes mellitus, and radiation injury in the dog.19,27 Delayed gastric emptying has also been associated with several secondary conditions, including electrolyte disturbances (e.g., hypokalemia, hypocalcemia), metabolic disorders (e.g., hypoadrenocorticism, hypergastrinemia, uremia), concurrent drug usage (e.g., cholinergic antagonists, -adrenergic agonists, opiates), acute stress (e.g., sympathetic stimulation, spinal cord injury), and acute abdominal inflammation.19,27

Diabetes mellitus is the most common endocrinopathy of the domestic dog.28 Long-standing un-diagnosed or un-treated diabetes mellitus is associated with significant gastroparesis in the dog,29,30 just as it in humans. The pathogenesis of gastroparesis in diabetes mellitus is complex and probably multi-factorial, involving one or more of the cellular elements (neurons, smooth muscle cells, interstitial cells of Cajal) regulating gastric motility.31 An important pathophysiologic mechanism appears to be the loss of neuronal nitric oxide synthase, the enzyme responsible for the production of nitric oxide, an inhibitory neurotransmitter that is required for relaxation of smooth muscle and therefore a critical component of normal gastrointestinal motility. In the absence of nitric oxide, the stomach cannot relax, resulting in bloating, satiety, nausea, and vomiting.32

Cisapride, metoclopramide, and erythromycin have all been used with variable effect in diabetic gastroparesis. Therapy aimed instead at restoring nitrergic neurotransmission could have intrinsic beneficial effects in canine diabetic gastroparesis. AMU-301, a nitric oxide (NO) donor, is recognized as an effective treatment for diabetic gastroparesis in streptozotocin-induced (STZ) diabetic rat models of delayed gastric emptying, and may eventually prove useful in spontaneous canine diabetes mellitus.

References:
1. Meyer JH. Motility of the stomach and gastroduodenal junction. In Johnson LR (ed): Physiology of the Gastrointestinal Tract, 2nd ed. New York, Raven Press, 1987, pp. 613-630.
2. Lammers WJEP, Ver Donck L, Stephen B, et al. Origin and propagation of the slow wave in the canine stomach: the outlines of a gastric conduction system. Am J Physiol 296: G1200-G1210, 2008.
3. de Vos WC. Migrating spike complex in the intestine of the fasting cat. Am J Physiol 265: G619-G627, 1993.
4. de Vos WC. Role of the enteric nervous system in the control of migrating spike complex in the feline intestine. Am J Physiol 265: G628-G637, 1993.
5. Gualtieri M, Monzeglio MG. Gastrointestinal polyps in small animals. Europ J Comp Gastro 1996; 1: 5-15.
6. Matthiesen DT, Walter MC. Surgical treatment of chronic hypertrophic pyloric gastropathy in 45 dogs. J Am Anim Hosp Assoc 1986; 22: 241-249.
7. Bellenger CR, Maddison JE, MacPherson GC, et al. Chronic hypertrophic pyloric gastropathy in 14 dogs. Aus Vet J 1990; 67:317-323.
8. Sikes RL, Birchard S, Patnaik A, et al. Chronic hypertrophic pyloric gastropathy: a review of 16 cases. J Am Anim Hosp Assoc 1986; 22: 99-106.
9. van der Gaag I. Hypertrophic gastritis in 21 dogs. Zentralbl Veterinarmed 1984; 31: 161-167.
10. Walter MC, Goldschmidt MH, Stone EA, et al. Chronic hypertrophic pyloric gastropathy as a cause of pyloric obstruction in the dog. J Am Vet Med Assoc 1985; 186: 157-164.
11. Biller DS, Partington BP, Miyabayashi T, et al. Ultrasonographic appearance of chronic hypertrophic pyloric gastropathy in the dog. Vet Radiol Ultrasound 1994; 35: 30-37.
12. Leib MS, Saunders GK, Moon ML, et al. Endoscopic diagnosis of chronic hypertrophic pyloric gastropathy in dogs. J Vet Intern Med 1993; 7: 335-341.
13. Miller RI. Gastrointestinal phycomycosis in 63 dogs. J Am Vet Med Assoc 1985; 186: 473-479.
14. Pier AC, Cabanes FJ, Ferreiro L, et al. Prominent animal mycoses from various regions of the world. Med Mycol 2000; 38: 47-62.
15. Grooters AM. Pythiosis, lagenidiosis, and zygomycosis in small animals. In, Veterinary Clinincs of North America 2003; 33:695-718.
16. Graham JP, Newell SM, Roberts GD, et al. Ultrasonographic features of canine gastrointestinal pythiosis. Vet Radiol & Ultrasound 2000; 41:273-280.
17. Grooters AM, Gee MK. Development of a nested polymerase chain reaction assay for the detection and identification of Pythium insidiosum. J Vet Intern Med 2002; 16:147-154.
18. Hall JA and Washabau RJ. Diagnosis and treatment of gastric motility disorders. In, Veterinary Clinics of North America 1999; 29(2): 377-395
19. Hall JA. Diseases of the stomach. In, Textbook of Veterinary Internal Medicine. 5th edition. Ed. Ettinger SJ and Feldman EC, WB Saunders Company, Philadelphia, pp 1118-1142.
20. Washabau RJ, Holt DE (2003a). Pathophysiology of Gastrointestinal Disease. In, Textbook of Veterinary Surgery. 3rd edition. Ed. D Slatter, WB Saunders Company, Philadelphia, pp 530-555.
21. Couto CG et al. Gastrointestinal lymphoma in 20 dogs. J Vet Intern Med 1989; 3: 73-79.
22. Kapatkin AS et al. Leiomyosarcomas in dogs. J Amer Vet Med Assoc 1992; 201: 1077-1984.
23. Rakich PM et al. Mucocutaneous plasmacytomas in the dog. J Am Vet Med Assoc 1989; 194:803-809.
24. Mahony OM, Moore AS, Cotter SM, et al. Alimentary lymphoma in cats. J Amer Vet Med Assoc 1995; 207: 1593-1602.
25. Washabau RJ. Diseases of the esophagus. In: Textbook of Veterinary Internal Medicine. 5th edition. Eds. SJ Ettinger and EC Feldman, WB Saunders Company, Philadelphia, 2000, pp 1142-1153.
26. Washabau RJ. Gastrointestinal motility disorders and gastrointestinal prokinetic therapy. In: Vet Clin N Amer 2003; vol, pp, WB Saunders Company, Philadelphia.
27. Nelson RW. Diabetes mellitus. In, Textbook of Veterinary Internal Medicine, Ettinger SJ and Feldman EC, eds. 6th edition. WB Saunders, Philadelphia, 2005, 1563-1591.
28. Takeda M, Mizutani Y, Tsukamoto K, et al. Gastric emptying in diabetic gastroparetic dogs: effects of DK-951, a novel prokinetic agent. Pharmacology 2001; 62: 23-28.
29. Koizumi F, Kawamura T, Ishimori A. Correlation between gastric emptying time and both plasma gastrin and pancreatic polypeptide in streptozotocin diabetic dogs. Japanese Journal of Gastroenterology 1989; 86: 1037-1043.
30. Camilleri M. Diabetic gastroparesis. New England Journal of Medicine 2007; 356: 820-829.
31. Pasricha PJ. The riddle, mystery, and enigma of gastroparesis. Journal of Supportive Oncology 2007; 5: 368-370.
32. Amulet Pharmaceuticals AMU-301 Fact Sheet. New Chemical Entity (NCE) for Diabetic Gastroparesis. http://www.amuletpharma.com/AMU-301_FACT_SHEET.pdf

Small Intestinal Motility Disorders

Intestinal Motility Patterns
Contractions in the small intestine serve three general functions – mixing of the ingesta with digestive enzymes and other secretions, circulation of the intestinal contents to facilitate contact with the intestinal mucosa, and net propulsion of the intestinal contents in an aborad direction. Intestinal contractions are governed by four motility patterns – segmentation, peristalisis, intestino-intestinal inhibition, and the migrating motility complex.

Segmentation – If a contraction is not coordinated with activity above and below, intestinal contents are displaced both proximally and distally during the contraction and may, in fact, propagate orad during the period of relaxation. Such contractions appear to divide the bowel into segments, which accounts for the term “segmentation” given to the process. Segmentation serves to mix and locally circulate the intestinal contents. Segmentation primarily involves circular smooth muscle contraction.

Peristalsis – The small intestine is capable of eliciting a highly coordinated contractile response that is propulsive in nature. When the bowel is distended by a bolus of food the bowel responds with contraction orad and relaxation aborad to the point of distension. The neurotransmitters involved in the orad contraction are acetylcholine (ACh) and substance P (SP), and the neurotransmitters involved in the caudad relaxation are vasoactive intestinal peptide (VIP) and nitric oxide (NO). These events tend to move the material in an aborad direction. Short segment peristalsis of the bowel is the norm in dogs and cats. If short segment peristalses occur sequentially they can propel a bolus the entire length of the gut in a short period of time. This peristaltic response, first characterized by Bayliss and Starling, is referred to as the “Law of the Intestine”, and is less frequent than short-segment peristalses.

Intestino-intestinal Inhibition – If an area of the bowel is grossly distended, contractile activity in the rest of the bowel is inhibited. This reflex prevents the movement of ingesta into more distal segments of intestine that have been severely distended or obstructed. This reflex is mediated by the extrinsic (autonomic) nervous system.2

Migrating Motility Complex – The migrating motility complex (MMC) propagates indigestible materials, mucus, and secretions from the stomach to the colon during the fasting state. The enteric nervous system regulates the periodicity and migration of the MMC, but the gastrointestinal hormone motilin reinforces the MMC activity. Cats do not have MMCs, and instead have a migrating spike complex (MSC) that is less vigorous than the canine MMC.2,3

Breed Differences in GI Transit Time

Significant differences in physiology and pharmacology have been found in dog breeds. There are over 400 breeds of dogs recognized worldwide and 156 breeds recognized by the American Kennel Club. Amongst these various dog breeds, several important differences in metabolism have been noted, e.g., p-glycoprotein-mediated metabolism, copper storage, and growth rates,5 Differences in GI transit characteristics have also been noted. The GI tract of large breed dogs (e.g., 60 kg) comprises 2.8% of their total body weight. In contrast, it comprises 7% of the total body weight of small breed dogs (e.g., 5 kg). Breed related differences in fecal water content could reflect differences in GI transit time, intestinal fermentation, diet, metabolism, and drug absorption. Using radio-opaque markers (1.5 mm diameter administered in food), 12 week old large breed puppries (e.g., Great Danes) exhibited a significantly longer oro-cecal transit time (OCTT; 3.4 hours) as compared to small breed puppies (e.g., Miniature poodle, 2.5 hours). The longer transit time appears to reflect both a longer gastric emptying time and a longer small intestinal transit time between breeds. There also appear to be differences in intestinal permeability between dog breeds. The lactulose/rhamnose ratio reflects the relative absorption across the intestinal tight junction (transcellular absorption) versus the intestinal surface area (paracellular absorption, which occurs across the cell membrane of the enterocyte). The L/R ratio is substantially greater in the Greyhound breed as compared to the Golden Retriever breed. Breed and age characteristics must be taken into account when differentiating normal and abnormal transit times.

Definition of Ileus
Ileus has been defined as the functional inhibition of propulsive bowel activity, irrespective of pathogenetic mechanism.6,7 There are several underyling causes of ileus, including dysautonomia, post-operative ileus, opioid-induced bowel dysfunction, muscular dystrophy, visceral myopathy, viral enteritis, radiation enteritis, idiopathic pseudo-obstruction, and hypothyroidism. Some ileus disorders are more readily treated than others.

DYSAUTONOMIA

Etiology
Dysautonomia is a generalized autonomic neuropathy that was originally reported in cats in the United Kingdom, but that has now been documented in dogs and cats throughout Western Europe and the United States.8-16 The clinical signs reflect a generalized autonomic dysfunction but megaesophagus, esophageal hypomotility, gastric and small bowel distension and hypomotility, and urinary bladder distension are fairly consistent findings.8,10,16 Aspiration pneumonia and megacolon are seen less frequently.

Pathophysiology
Degenerative lesions are found in autonomic ganglia, intermediate gray columns of the spinal cord, and some sympathetic axons.10,12,13 Despite an intensive search for genetic, toxic, nutritional, and infectious etiologic agents, no definitive etiology has ever been established.

Clinical Signs
Vomiting, diarrhea, anorexia, lethargy, weight loss, dysuria, and inspiratory dyspnea are the most frequent clinical signs reported in dogs. In cats, dilated pupils, esophageal dysfunction, dry nose, reduced lacrimal secretions, prolapse of the third eyelid regurgitation and constipation are the most frequent clinical signs.12

Diagnosis
A clinical diagnosis is made in most cases based on historical and physical examination findings. Additional findings consistent with the diagnosis would include: 1) esophageal dilation and hypomotility on survey or barium contrast radiographs; 2) delayed gastric emptying on barium contrast radiographs; 3) reduced tear production in Schirmer tear tests; 4) atropine-insensitive bradycardia; and, 5) bladder and colonic distention on survey radiographs. There are few differential diagnoses to consider in a dog or cat presenting with the myriad manifestations of the syndrome. Early in the course of the illness, however, other differential diagnoses to consider are colonic or intestinal obstruction, other causes of megaesophagus, and lower urinary tract disease.

Treatment
Supportive care (e.g. artificial tears, elevated feedings, expressing the urinary bladder, antibiotics, etc.) is still the basis of therapy in this disorder, although some dogs and cats are reported to show mild improvement with parasympathomimetic drugs (e.g. bethanechol or metoclopramide). Gastrostomy tube feedings or total parenteral nutrition may sustain some animals until they regain neurologic function.

Prognosis
In general, dysautonomia carries a guarded to poor prognosis for long-term survival in both the dog and the cat. 20 to 40% of affected cats are likely to recover, although cats may take 2 to 12 months to do so.12-16 Recovery rates are lower still in the dog.10,12 Complete recovery is uncommon and many cats and dogs are left with residual impairment, e.g. intermittent regurgitation, dilated pupils, and fecal or urinary incontinence

POST-OPERATIVE ILEUS

Etiology
Post-operative ileus has been defined as “ileus that develops following abdominal surgery, resolving spontaneously with 2 to 3 days”.17 It may be exacerbated by opioid administration during and following surgery. Multiple mechanisms have been proposed for the etiopathogenesis of post-operative ileus.17

Post-operative ileus is a significant problem in human medicine and constitutes the most important reason for delayed discharge from the hospital after abdominal surgery. The economic impact of post-ileus has been estimated to be $750 million to $1 billion in the United States. Similar data are not yet available in veterinary medicine.

Pathophysiology
Laparotomy and manipulation of the viscera are the main mechanisms underlying post-operative ileus, but other factors such as anesthetic agents and post-operative pain medication contribute to the delay in recovery of normal transit. The effect of general anesthetic agents is short lasting and therefore of only minor importance. The use of opioids to control post-operative pain has a much greater impact on post-operative motility. Post-operative opioids have significantly improved patient comfort in the early post-operative phase, but these drugs potently inhibit gastrointestinal transit. Efforts to reduce the dose of opioids or to antagonize their effects with peripherally acting opioid μ-antagonists such as methylnaltrexone or alvimopan are important to minimize the detrimental effect of opioids on gastrointestinal motility.

The main cause of post-operative ileus relates to the surgical procedure itself.17,18 The first (or neurogenic) phase is neurally-mediated and involves neural reflexes activated during and immediately following surgery. The second (or inflammatory) phase is triggered by the influx of leukocytes in manipulated intestinal segments and is responsible for the sustained inhibition of gastrointestinal motility.17

Clinical Examination
Nausea, vomiting, intestinal distension, and abdominal pain are the most important clinical signs of post-operative ileus in dogs and cats. Fever and leukocytosis may also be found depending upon the type and severity of abdominal surgery.

Diagnosis
The diagnosis of post-operative ileus is usually straight forward, and an exclusion of other known causes of ileus. Laboratory testing (complete blood count, serum chemistry, urinalysis) are sometimes performed to rule out metabolic disorders such as liver disease and renal failure. Abdominal imaging (e.g., survey radiography and ultrasonography) should be performed to exclude other causes of ileus and their complications, e.g., mechanical obstruction, peritoneal free air of fluid accumulation, and pancreatitis.

Treatment
Orogastric intubation – Intermittent orogastric or nasogastric intubation may be of benefit particularly in those patients with gaseous gastrointestinal distension.

Early post-operative feeding – Early post-operative feeding has been recommended as a means of decreasing the duration of post-operative ileus. Feeding may stimulate a reflex that coordinates propulsive activity and elicits the secretion of gastrointestinal hormones, causing an overall positive effect on bowel motility.

Laparoscopic procedures – Laparoscopic procedures offer the theoretical advantage of decreased tissue trauma compared with open abdominal procedures. This decrease in tissue trauma may lead to faster recovery of post-operative bowel function. Animal studies have found significant decreases in the duration of post-operative ileus after laparoscopic vs. open abdominal procedures.18

Prokinetic agents – Gastrointestinal prokinetic agents have a clear place in the management of post-operative ileus. These drugs and and their clinical usage are discussed in greater detail.

COX-II Inhibitors – Mechanical stretch in intestinal obstruction induces marked expression of COX-II in intestinal smooth muscle cells, and stretch-induced COX-II plays a critical role in the suppression of smoth muscle contractility in bowel obstruction.19 Therefore, COX-II inhibitors may have therapeutic potential in stretch-related disorders of the gut.

Opioid μ-antagonists – Opioid μ-antagonists like alvimopan and methylnaltrexone may be useful in antagonizing the effects of morphine-like opioid agonists if that is part of the underlying pathogenesis of post-operative ileus.20,21

Electrical stimulation – Although not yet clinically applicable, gastrointestinal pacing is achievable in the canine stomach and small intestine (but not the colon).22-26 The maximal entrainable frequency of the gastric and small intestinal slow waves is about 20% higher than the intrinsic frequency. In the future, stimulation parameters may be identified that will entrain slow waves thereby normalizing gastric and intestinal dysrhythmias.22-26

Prognosis
The prognosis for short term post-operative ileus is generally good to excellent. In animals with complicated, refractory post-operative ileus, the prognosis is less clear. More aggressive therapies may be needed in this patient population. In such cases, intestinal failure may result culminating in intestinal transplantation as a last resort.27,28,29

OPIOID-INDUCED BOWEL DYSFUNCTION

Etiology
Opioid-induced bowel dysfunction may be part of a post-operative ileus syndrome, or it may relate solely to the use of opioid μ,δ-agonists as part of an analgesic therapeutic regimen. Opioids are a mainstay in the treatment of acute and chronic pain. Although opioids are very effective for pain relief from cancer and other non-malignant diseases, their use is often limited by side effects. The most common adverse side effects are constipation and vomiting, but they also alter small bowel function causing opioid-induced bowel dysfunction. Opioid-induced bowel dysfunction can occur immediately after the first dose and persist for the duration of therapy. The peripherally acting μ–receptor antagonists methylnaltrexone and alvimopan are a new class of agents designed to reverse opioid-induced side effects on the gastrointestinal tract without compromising pain relief.31-36

Pathophysiology
Endogenous opioids include endorphins, enkephalins, and dynorphins. They act selectively at opioid receptors composed of the μ, δ, and κ sub-types. Opioid μ receptors are present in the central and peripheral nervous system, as well as the GI tract. There are many species and site differences, but μ receptors have been reported on the interstitial cells of Cajal, smooth muscle, and epithelial cells. The predominant opioid effect appears to be at the local level and includes stimulation of absorption (villus epithelial cells), inhibition of secretion (crypt epithelial cells), increased segmentation (circular smooth muscle), and reduced peristalsis (longitudinal smooth muscle). Exogenously administered opioids have the same overall effect of opioid inhibition of peristalsis and secretion leading to the syndrome of opioid-induced bowel dysfunction.31,32

Clinical Examination
Constipation and vomiting are the primary clinical signs of opioid-induced bowel dysfunction. Left untreated, constipation can progress to fecal impaction and mechanical obstruction.

Diagnosis
The patient usually has a well documented history of opioid μ-agonist therapy, e.g., morphine, in the management of a pain syndrome. Still, it would be important to rule out other causes of ileus, metabolic disorders, and mechanical obstruction. Therefore, the minimum database should include laboratory data (complete blood count, serum chemistry, urinalysis) and imaging (survery abdominal radiography or ultrasonography).

Treatment
In most instances, discontinuation of the opioid μ–agonist is sufficient to ameliorate clinical signs. With persistence of clinical signs after drug withdrawal, laxative (reviewed in Chapter 51) and other therapies may be used to treat constipation, although it should be emphasized that a definitive role in the treatment of opioid-induced bowel dysfunction has not yet been proved. Any of the laxative agents (bulk, lubricant, osmotic, stimulant, emollient – Chapter 51) could be used to attenuate the constipating effect of the opioid μ–agonist. Misoprostol, a synthetic prostaglandin E analog could also be used to improve intestinal and colonic transit times.36

If the central analgesic effect of the opioid μ–agonist is paramount, the patient could be treated concurrently with an opioid μ–antagonist, methylnaltrexone or alvimopan, both of which will improve GI transit without inhibiting the central analgesic effect of the opioid μ–agonist. In dogs, methylnaltrexone at a dose range of 1.0-5.0 mg/kg subcutaneously abolishes the effect of morphine on GI transit without interfering with the central analgesic effect.32 Safe and effective doses of alvimopan have not yet been reported in the dog.

If morphine must be used pre-operatively, the epidural route (vs. continuous low dose infusion) facilitates the time of appearance of the first gastric interdigestive migrating complex (the MMC) in dogs with paralytic ileus after open abdominal surgery.37

Prognosis
The prognosis for acute opioid-induced bowel dysfunction is generally good to excellent. Chronic opioid-induced bowel dysfunction may persist and therefore has a more guarded prognosis.

MUSCULAR DYSTROPHY

Etiology
Duchenne-type muscular dystrophy in the Golden Retriever dog is an X-linked genetic disorder that is characterized primarily by progressive muscular weakness. Involvement of the GI tract is frequent and may occur at any level from stomach to intestine and colon.38 The disorder is caused by mutations in the dystrophin gene responsible for production of the dystrophin membrane protein.39 The absence of dystrophin is accompanied by alteration of the dystrophin-glycoprotein complex (DCG) and results in progressive degeneration of the heart, skeletal and smooth muscle with subsequent replacement by fibrosis and fatty infiltration.

Pathophysiology
The gastroenterologic clinical signs have been attributed to motility disorders caused by smooth muscle damage, but histologic evidence of alterations has not been a consistent finding. In a more recent report, Golden Retriever dogs affected with Duchenne-type muscular dystrophy had marked degenerative lesions in the smooth musclulature of the GI tract, urinary, and reproductive systems. GI smooth muscle lesions were associated with the clinical findings of gastroparesis, gastric dilatation, and intestinal pseudo-obstruction.38

Clinical Signs
Dysphagia, regurgitation, gastroparesis, abdominal pain, and intestinal distension have been reported in affected animals. Gastroenterologic clinical signs may be the first sign of dystrophic disease and may precede the appendicular musculoskeletal features. The impairment of GI function may be gradual and undetected by the pet owner, breeder, or veterinarian.38

Diagnosis
Definitive diagnosis may be confirmed on the basis of history and physical examination findings, serum creatine kinase activity, genomic DNA analysis, muscle electrophysiology, gross morphology, and histological features.39 Ileus may be difficult to detect in the whole animal and may require the use of endoscopy, ultraonography, and scintigraphy.

Treatment
Despite major advances in our understanding of the pathophysiology of the disease, therapy is still largely supportive and symptomatic. Gene replacement therapy has not yet succeeded in restoring muscle function or in prolonging life.

Prognosis
At the present time, the prognosis for cure is poor. With supportive and symptomatic therapy, some affected animals have survived out to 51 months.38

VISCERAL MYOPATHY
One case of visceral myopathy in a six month old DSH cat has been reported in the veterinary literature.40 The kitten had a 6-day history of anorexia, intermittent vomiting, and diarrhea, and severely dilated loops of hypomotile intestine were found on survey abdominal radiography and ultrasonography. Intestinal dilation was confirmed at the time of surgery, and a 20-cm section of jejunum was resected. In the proximal jejunum, there was marked atrophy of the longitudinal muscle of the muscularis externa layer and diffuse severe degenerative vacuolar change within the myocytes and endomysial cells. The circular muscle layer was of normal thickness and morphology. Villus stunting and fusion were evident in the mucosa. In the distal jejunum, the mucosa and submucosa were normal, but the longitudinal muscle layer was markedly atrophic with focal degeneration, calcification, loss of myocytes, and replacement by proliferating fibroblasts. Based upon descriptions of human visceral myopathy, the findings were thought to be consistent with a diagnosis of visceral myopathy causing chronic intestinal pseudo-obstruction.40 The cat was alive and doing well twenty months after surgery.

PARVOVIRAL ENTERITIS
Ileus is a frequent finding in puppies affected with parvoviral enteritis.41 The ultrasonographic appearance of the gastrointestinal tract was characterized in forty puppies with confirmed canine parvoviral enteritis.41 Sonographic findings included fluid-filled small intestines in 92.5% of the cases (see Figure 57-3), and of the stomach and colon in 80% and 62.5% of the cases, respectively. Generalized atony was present in 75% of the cases, and weak peristaltic contractions indicative of functional ileus were observed in the remaining 25% of cases. The duodenal and jejunal mucosal layer thicknesses were significantly reduced when compared with normal puppies with mean duodenal mucosal layer measuring 1.7mm and jejunal mucosal layer 1.0mm. A mucosal layer with diffuse hyperechoic speckles was seen in the duodenum (15%) and the jejunum (50%). The luminal surface of the duodenal mucosa was irregular in 22.5% and the jejunal mucosa in 42.5%. Changes were accompanied by generalized indistinct wall layering.in all animals. A mortality rate of 30% was found in this patient population.41

RADIATION ENTERITIS
Radiation produces a variety of changes in gastrointestinal tract motility and ileus is a common clinical finding.42 Most of the changes observed with radiation enteritis occur in other pathologic states. These include delayed gastric emptying, retrograde giant contractions (RGCs) and vomiting, giant migrating contractions (GMCs), and abdominal cramping and diarrhea.43 The threshold for these contractile events to occur and their control mechanisms are incompletely understood. Many studies suggest that treatment (i.e., 5-HT3 antagonists) prior to exposure may be the best method to prevent the contractions from occurring. The role of dose rate is unclear. Within hours of a significant exposure to radiation, these contractions begin to occur and contribute significantly to the early stages of radiation illness.

IDIOPATHIC INTESTINAL PSEUDO-OBSTRUCTION

Etiology
Chronic intestinal pseudo-obstruction is defined by the presence of chronic intestinal dilatation and dysmotility in the absence of mechanical obstruction.44 In humans, chronic intestinal pseudo-obstruction has many causes which have been simplified into abnormalities of enteric smooth muscle (myopathies) and the enteric nervous system (neuropathies).40 Such visceral myopathies and neuropathies are primary causes of chronic intestinal pseudo-obstruction, and myopathies are either familial, or sporadic and idiopathic. Pseudo-obstruction can also arise secondary to other underlying disorders, such as progressive systemic sclerosis, amyloidosis, muscular dystrophy, generalized neuromuscular diseases, endocrinopathies, infectious disease, and drug toxicity.40

Pathophysiology
Only eleven cases of chronic intestinal pseudo-obstruction have been reported in companion animals (9 dogs and 2 cats).44-49 Four dogs had atrophy, fibrosis, and mononuclear cell infiltration of the muscularis externa similar to what is observed in progressive systemic sclerosis in humans. Two dogs had atrophy of the muscularis externa but not fibrosis, either with or without mononuclear cell infiltration, whereas one dog had hyperplasia of the circular muscle without atrophy, fibrosis, or inflammation. In only 2 reported dogs with pseudo-obstruction, the pathology described as primarily affecting the circular muscle the longitudinal muscle. Only 2 report mentions myocyte vacuolar degeneration, but it was not a p;rominent feature and marked myenteric plexus vacuolar degeneration was present, suggesting an underlying primary neuropathy. One of the cats reported with pseudo-obstruction actually had diffuse intestinal lymphosarcoma with no additional histopathologic details.

Clinical Signs
As with visceral myopathy, the primary clinical signs seen with chronic intestinal pseudo-obstruction are anorexia, intermittent vomiting, and diarrhea. Signs may be referable to one segment of the gut, but the disease us usually diffuse.

Diagnosis
Abdominal imaging showing intestinal dilatation with no evidence of mechanical obstruction is the hallmark of the pseudo-obstruction. Full-thickness intestinal histology is required to identify underlying causes of chronic intestinal pseudo-obstruction.

Treatment
Because of the diffuse nature of the disease, surgical resection of diseased intestine is not generally recommended. Resection only benefits selected patients with localized disease. Medical therapy should otherwise be aimed at correcting electrolyte and acid/base disturbances, treating infection or sepsis, supporting nutritional needs, suppressing the inflammatory or immune response, and instituing prokinetic therapy (see Chapter 53).44-49

Prognosis
Aside from the apparent recovery reported in one cat with visceral myopathy, most of the cases of chronic intestinal pseudo-obstruction had a poor outcome.

HYPOTHYROIDISM
Untreated or poorly regulated hypothyroidism has been associated with important changes in gastrointestinal motility. Compared to euthyroid dogs, thyroidectomized dogs have decreased frequency of electrical control activity of the stomach and jejunum, decreased occurrence of electrical response activity (spike potentials) following stimulation, and decreased mechanical response to feeding.50

REFERENCES
1. Weisbrodt NW. Motility of the small intestine. In Johnson LR (ed): Physiology of the Gastrointestinal Tract, 2nd ed. New York, Raven Press, 1987, pp. 631-664.
2. Mishra NK, Appert HE, Howard JM. The effects of distention and obstruction on the accumulation of fluid in the lumen of small bowel of dogs. Ann Surg 180: 791-795, 1974.
3. de Vos WC. Migrating spike complex in the intestine of the fasting cat. Am J Physiol 265: G619-G627, 1993.
4. de Vos WC. Role of the enteric nervous system in the control of migrating spike complex in the feline intestine. Am J Physiol 265: G628-G637, 1993.
5. Fleischer S, Sharkey M, Mealey K, et al. Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model. AAPS Journal 10: 110-119. 2008.
6. Camilleri M, Bueno L, de Ponti F, et al. Pharmacological and pharmacokinetic aspects of functional gastrointestinal disorders. Gastro 130: 1421-1334, 2006.
7. Wood JD. Neuropathophysiology of functional gastrointestinal disorders. World J Gastro 13: 1313-1332, 2007.
8. Berghaus RD, O’Brien DP, Johnson GC, et al. Risk factors for development of dysautonomia in dogs. J Am Vet Med Assoc 218: 1285-1290, 2001
9. Detweiler DA, Biller DS, Hoskinson JJ, et al. Radiographic findings of canine dysautonomia in twenty-four dogs. Vet Radiol & Ultrasound 42: 108-112, 2001.
10. Harkin KR, and Andrews GA, and Nietfeld JC. Dysautonomia in dogs: 65 cases (1993-2000). J Am Vet Med Assoc 220: 633-639, 2002.
11. Harkin KR, Nietfeld J, and Fischer JR. Dysautonomia in a family of German shorthaired pointers. JAAHA 38: 55-59, 2002.
12. O’Brien DP and Johnson GC. Dysautonomia and autonomic neuropathies. Vet Clin N Amer – Small Anim Pract. 32: 251-265, 2002.
13. Sharp NJH. Feline dysautonomia. Semin Vet Med Surg 5: 67-71, 1990.
14. Kidder AC, Johannes C, O’Brien DP, et al. Feline dysautonomia in the Midwestern United States: a retrospective study of nine cases. J Fel Med Surg 10: 130-136, 2007.
15. Cave TA, Knottenbelt C, Mellor DJ, et al. Outbreak of dysautonomia in a closed colony of pet cats. Vet Rec 153: 387-392, 2003.
16. Novellas R, Simpson KE, Gunn-Moore DA, et al. Imaging findings in 11 cats with dysautonomia. J Fel Med Surg 12: 584-591, 2010.
17. Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. Gut 58: 1300-1311, 1009.
18. Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg 138: 206-214, 2003.
19. Shi XZ, Lin SY-M, Powell DW, et al. Pathophysiology of motility dysfunction in bowel obstruction: role of stretch-induced COX-2. Am J Physiol (Gastrointest Liver Physiol) 300: G99-G108. 2011.
20. DeHaven-Hudkins DL, DeHaven R, Little PJ, et al. The involvement of the μ-opioid receptor in gastrointestinal pathophysiology: therapeutic opportunities for antagonism at this receptor. Pharm Toxicol 117: 162-187, 2008.
21. Becker G, Bluim HE. Novel opioid antagonists for opioid-induced bowel dysfunction and post-operative ileus. Lancet 373: 1198-1206, 2009
22. Sun Y, Song GQ, Lei Y, et al. Effects and mechanisms of gastrointestinal electrical stimulation on slow waves: a systematic canine study.
23. Huibin Q, Chen JDZ. Effects of intestinal electrical stimulation on postprandial small-bowel motility and transit in dogs. Am J Surg 192: e55-e60, 2006.
24. Yin J, Chen JDZ. Excitatory effects of synchronized intestinal electrical stimulation on small intestinal motility in dogs. Am J Physiol (Gastrointest. Liver Physiol) 293: G1190-G1195, 2007.
25. Yin J, Chen JDZ. Mechanisms and potential applications of intestinal electrical stimulation. Dig Dis Sci 55: 1208-1220, 2010.
26. Xu X, Lei Y, Chen JDZ. Effects and mechanisms of electrical stimulation of the stomach, duodenum, ileum, and colon on gastric tone in dogs. Dig Dis Sci 55: 895-901, 2010.
27. Todo S, Tzakis A, Abu-Elmagd K, et al. Current status of intestinal transplantation. Adv Surg 27: 295-316, 1994.
28. Bines JE. Intestinal failure: a new era in clinical management. J Gastro Hepatol 24: S86-S92, 2009.
29. Belkind-Gerson J, Graeme-Cook F, Winter H. Enteric nervous system disease and recovery, plasticity, and regeneration. J Ped Gastroenterol Nutr 42: 343-350, 2006.
30. Thomas J. Opioid-induced bowel dysfunction. J Pain Symp Management 35: 103-113, 2008.
31. Becker G, Blum HE. Novel opioid antagonists for opioid-induced bowel dysfunction and post-operative ileus. Lancet 373: 1198-1206, 2009.
32. Fukuda H, Suenaga K, Tsuchida D, et al. The selective mu opioid receptor antagonist, alvimopan, improves delayed GI transit of postoperative ileus in rats. Brain Research 2006.
33. Yuan C-S. Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacotherapy 41: 984-993, 2007.
34. Viscusi ER, Gan TJ, Leslie JB, et al. Periphierally acting mu-opioid receptor antagonists and postoperatie ileus: mechanisms of action and clinical applicability. Anesth Analg 108; 1811-1822, 2009.
35. Leslie JB. Alvimopan for the management of postoperative ileus. Ann Pharmacotherapy 39: 1502-1510, 2005.
36. Washabau RJ.
37. Nakayoshi T, Kawasaki N, Suzuki Y, et al. Epidural administration of morphine facilitates time of appearance of first gastric interdigestive migrating complex in dogs with paralytic ileus after open abdominal surgery. J Gastrointest Surg 11: 648-654, 2007.
38. Iyazato LG, Beretta DC, Engracia-Filho JR, et al. Involvement of organic systems in golden retriever X-linked muscular dystrophy. Braz J Vet Path 4: 87-94, 2011.
39. Bellini M, Biagi SG, Stasi C, et al. Gastrointestinal manifestations in myotonic muscular dystrophy. World J Gastro 12: 1821-1828, 2006.
40. Bettini G, Muracchini M, Della Salda L, et al. Hypertrophy of intestinal smooth muscle in cats. Res Vet Sci 75: 43-53, 2003.
41. Stander N, Wagner WM, Goddard A, et al. Veterinary Radiology & Ultrasound 51; 2010, 69–74, 2010.
42. Summers RW, Glenn CE, Flatt AJ et al. Does irradiation produce irreversible changes in canine jejunal myoelectric activity? Dig Dis Sci 27; 716-722, 1992.
43. Otterson MF. Effects of radiation upon gastrointestinal motility. World J Gastroenterol 13: 2684-2692, 2007.
44. Harvey AM, Hall EJ, Day MJ, et al. Chronic intestinal pseudo-obstruction in a cat caused by visceral myopathy. J Vet Intern Med 19: 111-114, 2005.
45. Couraud L, Jermyn K, Yam PS, et al. Intestinal pseudo-obstruction, lymphocyticleiomyositis and atrophy of the muscularis externa in a dog. Vet Rec 159: 86-87, 2006.
46. Johnson CS, Fales-Williams AJ, Reimer SB, et al. Fibrosing gastrointestinal leiomyositis as a cause of chronic intestinal pseudo-obstruction in an 8-month old dog. Vet Pathol 44: 106-109, 2007.
47. Eastwood JM, McInnes EF, White RN, et al. Caecal impaction and chronic intestinal pseudo-obstruction in a dog. J Vet Med 52: 43-44, 2005.
48. Lamb WA, France MP. Chronic intestinal pseudo-obstruction in a dog. Aus Vet J 71; 84-86, 1994.
49. Dvir E, Leisewitz AL, Van Der Lugt JJ. Chronic idiopathic intestinal pseudo-obstruction in an English bulldog. JSAP 42: 243-252, 2001.
50. Daher R, Yazbeck T, Jaoude JB, et al. Consequences of dysthyroidism on the digestive tract and viscera. World J Gastroenterol 21: 2834-2838, 2009.

Table 57-1. Pathophysiologic mechanisms of post-operative ileus

Mechanisms Factors Involved
Autonomic nervous system Sympathetic inhibitory pathways
Enteric nervous system Substance P, nitric oxide
Hormones and neuropeptides Vasoactive intestinal peptide; corticotrophin-releasing
factor ligands; calcitonin gene-related peptide ligands
Inflammation Macrophage and neutrophil infiltration; cytokines and other
inflammatory mediators
Anesthesia General anesthetics
Narcotics Opiates

Box 57-1. Causes of intestinal dysmotility in dogs and cats

Dysautonomia
Post-operative ileus
Opioid-induced bowel dysfunction
Muscular dystrophy
Visceral myopathy
Viral enteritis
Radiation enteritis
Idiopathic pseudo-obstruction
Hypothyroidism

Gastrointestinal Prokinetic Agents

INTRODUCTION
Gastrointestinal motility disorders represent a diagnostic and therapeutic challenge. Disorders of gastrointestinal motility may result in delayed transit, accelerated transit, impaired relaxation, or inappropriate relaxation. The delayed transit disorders are the most important motility disorders of companion animals and may involve the esophagus (hypomotility and megaesophagus), stomach (delayed gastric emptying), small intestine (post-operative ileus and intestinal pseudo-obstruction), or colon (constipation and megacolon).

DOPAMINERGIC D2 ANTAGONIST DRUGS (Table 52.1)
Metoclopramide and Domperidone – The dopaminergic D2 antagonists are a group of drugs with gastrointestinal prokinetic and antiemetic effects at peripheral (prokinetic) or central (antiemetic) dopamine D2 receptors.1 The best representatives in this classification, metoclopramide and domperidone, reverse gastric relaxation induced by dopamine infusion in dogs, and they abolish vomiting associated with apomorphine therapy. Although the role of dopamine receptors in chemoreceptor trigger zone-induced vomiting is fairly well established, there is no definitive evidence that inhibitory dopaminergic neurons regulate gastrointestinal motility. The prokinetic effects of metoclopramide and domperidone thus may not be readily or exclusively explained by dopamine receptor antagonism. Some dopaminergic antagonists (e.g., metoclopramide) have other pharmacologic properties, e.g., 5-HT3 receptor antagonism and 5-HT4 receptor agonism. Domperidone also has 2- and 2-adrenergic receptor antagonistic effects. The characterization of these drugs as dopaminergic antagonists is convenient but may not properly describe their overall in vivo effects.

Gastroesophageal Sphincter Disorders
The gastroesophageal sphincter prevents reflux of gastrointestinal contents into the esophageal body.2,3 Reflux of gastric H+ and pepsins, and of duodenal bicarbonate, bile salts, and proteases, induces chemical injury and inflammation of the esophageal mucosa.3 Gastroesophageal sphincter tone appears to be under the regulation of dopaminergic neurons as both metoclopramide and domperidone increase sphincter tone. The gastric prokinetic effect of metoclopramide, although moderate, may also help to reduce the frequency, severity, and duration of reflux episodes.

Gastric Emptying Disorders
Metoclopramide increases the amplitude and frequency of antral contractions; inhibits fundic receptive relaxation; and coordinates gastric, pyloric, and duodenal motility, all of which result in moderate acceleration of gastric emptying.4,5 Metoclopramide appears to have continuing clinical application as a gastric prokinetic agent in the dog and cat, although the serotonergic agonists are clearly more potent. Domperidone appears to be less effective as a gastric prokinetic agent. Although effective in humans, domperidone actually decreases the frequency of corporeal, pyloric, and duodenal contractions and deteriorates antropyloroduodenal coordination in the dog by decreasing the frequency of contractions spreading from the antrum or pylorus to the duodenum.5

Small Intestinal Transit Disorders
Metoclopramide and domperidone are generally considered less effective in the management of the small intestinal transit disorders. Metoclopramide enhances antropyloroduodenal coordination in the dog and may be effective when delayed gastric emptying is due to poor antropyloroduodenal coordination.6 Domperidone has no documented effects on small intestinal transit.

Chemoreceptor trigger zone-induced emesis
The antiemetic effects of metoclopramide and domperidone are attributed to their central effects at the chemoreceptor trigger zone.7 The anti-emetic effect of metoclopramide is more important than its prokinetic effect.1,7 Despite longstanding usage by small animal veterinarians, metoclopramide is not a very potent gastrointestinal prokinetic agent. Domperidone is 12 to 25 times more potent than metoclopramide and 50 to 60 times more potent than prochlorperazine in attenuating apomorphine-induced vomiting.

SEROTONERGIC 5-HT4 AGONIST DRUGS (Table 52.1)
Drugs acting on gastrointestinal 5-hydroxytryptamine (5-HT or serotonin) receptors have potent motility effects.8 Serotonergic drugs that bind 5-HT4 receptors on enteric cholinergic neurons induce depolarization and contraction of gastrointestinal smooth muscle. These drugs are not entirely selective for the 5-HT4 receptor, however. Some of the putative 5-HT4 receptor agonists also have 5-HT1 and 5-HT3 antagonistic effects on enteric cholinergic neurons, and direct non-cholinergic (perhaps 5-HT2a) effects on colonic smooth muscle. Cisapride, mosapride, prucalopride, and tegaserod are the best examples in this classification. Cisapride and tegaserod have been withdrawn from several international markets because of their effect(s) on myocardial Q-T internal prolongation, although both remain available through compounding pharmacies. Mosapride is available in Japan (Pronamid – DS Pharma), and prucalopride is available in Europe (Resolor – Movetis).

Cisapride – Cisapride was widely used in the management of canine and feline gastric emptying, intestinal transit, and colonic motility disorders throughout most of the 1990’s.9,10 Cisapride was withdrawn from the American, Canadian and certain Western European in July of 2000 following reports of untoward cardiac side effects in human patients. Cisapride causes QT interval prolongation and slowing of cardiac repolarization via blockade of the rapid component of the delayed rectifier potassium channel (IKr).11 This effect may result in a fatal ventricular arrhythmia referred to as torsades de pointes.11 Similar effects have been characterized in canine cardiac Purkinje fibers, but in vivo effects have not been reported in dogs or cats. The withdrawal of cisapride has created a clear need for new G.I. prokinetic agents although cisapride continues to be available from compounding pharmacies.

Gastroesophageal Sphincter Disorders
Cisapride is indicated for the treatment of gastroesophageal reflux because it stimulates gastric emptying and increases gastroesophageal sphincter pressure. Comparative studies have shown that cisapride is more potent than metoclopramide in stimulating gastric emptying and increasing gastroesophageal sphincter pressure. Cisapride can be used in conjunction with chemical diffusion barriers (e.g., sucralfate) and gastric acid secretory inhibitors (e,g., H2 receptor antagonists; H+,K+ ATPase inhibitors) in the treatment of gastroesophageal reflux.12-14 Cisapride stimulates distal esophageal peristalsis in those animal species (e.g., cat, human being, guinea pig) in which the distal esophageal muscularis is composed of smooth muscle. The obvious exception is the dog, a species in which the entire esophageal body is composed of striated muscle. It has been suggested that cisapride might improve esophageal peristalsis in dogs affected with idiopathic megaesophagus. This would not appear to be a rational clinical application of the drug, because a smooth muscle prokinetic agent would not be expected to have much effect on striated muscle function. Indeed, the prokinetic effect of cisapride in the esophagus of human beings or cats is confined to the distal esophageal body at the transition zone from striated muscle to smooth muscle. Cisapride has no effect on proximal esophageal peristalsis in these species. Further, 5-HT stimulates contraction of canine gastroesophageal sphincter smooth muscle, but is without effect on canine esophageal body striated muscle.15 Thus, cisapride cannot be recommended for the treatment of idiopathic megaesophagus in dogs. Indeed, cisapride-induced increases in gastroesophageal sphincter pressure could diminish esophageal clearance and worsen clinical signs in dogs affected with idiopathic megaesophagus.

Gastric Emptying Disorders
Cisapride accelerates gastric emptying in dogs by stimulating pyloric and duodenal motor activity, by enhancing antropyloroduodenal coordination, and by increasing the mean propagation distance of duodenal contractions.5,16 Cisapride appears to be superior to metoclopramide and domperidone in stimulating gastric emptying. Dosages of cisapride in the range of 0.05-0.2 mg/kg enhance gastric emptying in dogs with normal gastric emptying. Dosages in the range of 0.5-1.0 mg/kg are needed to enhance gastric emptying in dogs with delayed gastric emptying induced by α2-adrenergic agonists, dopamine, disopyramide, or antral tachygastria.9,10

Small Bowel Motility Disorders
Cisapride stimulates jejunal spike burst migration, jejunal propulsive motility, and antropyloroduodenal coordination following intestinal lipid infusion in the dog.6,17 Thus, cisapride would appear to have a rational place in the treatment of post-operative ileus and intestinal pseudo-obstruction. Well-designed clinical trials and evidence-based data will be required to determine the effectiveness of cisapride in the treatment of these disorders.

Colonic Motility Disorders
Cisapride stimulates colonic motility,18,19 and would appear to have a rational place in the treatment of idiopathic constipation. Disruption of the normal colonic motility patterns results in constipation in domestic cats. Cisapride improves colonic motility in cats that are mildly or moderately affected with idiopathic constipation; cats with long-standing hypomotility and dilation are usually less responsive. A recent evidence-based data review of cisapride’s efficacy in the treatment of human constipation and constipation-predominant irritable bowel syndrome (IBS) was carried out by the Cochrane Collaboration.20 The authors concluded that “no clear benefit could be demonstrated with cisapride”.20

Cis-platinum-Induced Emesis
Cisplatinum-induced emesis is mediated by 5-HT3 serotonergic receptors, either in the chemoreceptor trigger zone (cat) or in vagal afferent neurons (dog). Selective antagonists of the 5-HT3 receptor (e.g., ondansetron, granisetron, tropisetron, dolasetron) abolish vomiting associated with cis-platinum chemotherapy. Cisapride antagonizes these 5-HT3 receptors and inhibits vomiting associated with cis-platinum chemotherapy. The potency of cisapride’s 5-HT3 anti-emetic effect (ED50 = 0.6 mg/kg IV; ED100 = 2.6 mg/kg IV) is less than its 5-HT4 gastric prokinetic effect. Thus, cisapride could be recommended as an antiemetic agent for the cancer chemotherapy patient only if ondansetron, granisetron, tropisetron, or dolasetron were not immediately available or were too cost-prohibitive.7 Metoclopramide is equipotent with cisapride in inhibiting cisplatinum emesis, but it has the distinct disadvantage of adverse central nervous system side effects, e.g. drowsiness, extreme weakness, and body tremors. Cisapride has no effect on nausea and vomiting mediated by dopaminergic D2 receptors (e.g. apomorphine, uremia) or histaminergic H1 receptors (e.g. motion sickness).

Mosapride – Mosapride citrate, a substituted benzamide, is a novel 5-HT4 receptor agonist that increases gastric emptying in rats and dogs, and increases electrically-evoked contractions in the isolated guinea pig ileum.21-22 Mosapride stimulates acetylcholine release from the myenteric plexus via activation of 5-HT4 receptors, but has no real affinity for D2 dopamine, 5-HT1, 5-HT2 receptors, or α1-adrenoceptors. Mosapride restores gastric motility in dogs with vincristine-induced gastric hypomotility,23 and therefore may be clinically useful in other gastric emptying disorders. Mosapride is apparently without effect on distal gastrointestinal tract motility. Mosapride is marketed as Pronamid by DS Pharma Animal Health in Japan.

Prucalopride – Prucalopride is a potent partial benzamide agonist at 5-HT4 receptors, but is without effect on other 5-HT receptors or cholinesterase enzyme activity. Prucalopride dose-dependently (0.02-1.25 mg/kg) stimulates giant migrating contractions (GMC’s) and defecation in the dog.24-26 The prucalopride effect is observed most prominently in the first hour after administration, suggesting that the prucalopride effect is a direct effect on the colon rather than on total gut transit time. Oral and intravenous doses appear to be equipotent again implying a high oral bioavailability. Prucalopride also enhances defecation frequency in healthy cats.27 Cats treated with prucalopride at a dose of 0.64 mg/kg experience increased defecation within the first hour of administration. Fecal consistency is not altered by prucalopride at this dosage.
Prucalopride also appears to stimulate gastric emptying in the dog.28 In lidamidine-induced delayed gastric emptying in dogs, prucalopride (0.01-0.16 mg/kg) dose-dependently accelerates gastric emptying of dextrose solutions. The prucalopride effect is equipotent following oral and intravenous administration suggesting that prucalopride may have a high oral bioavailability. Prucalopride is marketed as Resolor by Movetis in Europe.

Tegaserod – Tegaserod is a potent partial non-benzamide agonist at 5-HT4 receptors and a weak agonist at 5-HT1D receptors.29,30 Tegaserod has prokinetic effects in the distal gastrointestinal tract. Intravenous doses of tegaserod (0.03-0.3 mg/kg) accelerate colonic transit in dogs during the first hour after intravenous administration.29 The highest doses of tegaserod (0.1 and 0.3 mg/kg) have no greater efficacy than lower doses (0.03 mg/kg), suggesting the possibility that tegaserod may stimulate canine colonic motility through a receptor-independent mechanism, or that tegaserod may act at sites other than 5-HT4 receptors at higher doses.
The motor mechanisms responsible for tegaserod-induced canine colonic propulsion are unclear. High amplitude propagated phasic contractions are thought to be responsible for mass movements, but they were not observed during tegaserod infusion. Contraction, amplitude, and motility indices were not different postprandially among treatment groups, so the mechanism of the tegaserod effect will require more detailed investigation in the dog.
Gastric effects of tegaserod have not been reported in the dog, so this drug may not prove as useful as cisapride in the treatment of delayed gastric emptying disorders. Tegaserod at doses of 3-6 mg/kg PO has been shown to normalize intestinal transit in opioid-induced bowel dysfunction in dogs,31 and it may be useful in other disorders of intestinal ileus or pseudo-obstruction.
Tegaserod was approved by the U.S. Food and Drug Administration in September 2002, but later removed from the American market in 2007 because of reports of prolongation of the Q-T interval and delayed cardiac repolarization. Tegaserod is marketed as Zelnorm by Novartis in Europe.\

Future Research in 5-HT Receptor Pharmacology
The 5-HT4 receptor appears to hold the most interest and promise for future drug development. 5-HT4 receptor activation can cause relaxation or contraction depending on the region, cell type, and animal species. In the dog, the effects of selective 5-HT4 receptor agonists suggest that these receptors are present on jejunal mucosa, ileal mucosa, gastric cholinergic neurons, and circular colonic smooth muscle cells. Development of 5-HT4 ligands is somewhat constrained by the effects these drugs have on cardiac 5-HT4 receptors and the delayed rectifier potassium channel (IKr). Some, but not all, 5-HT4 agonists prolong the QT interval and delay cardiac repolarization. Molecular biology experiments have revealed differences in the carboxyl terminus of smooth muscle and cardiac muscle 5-HT4 receptors, but these amino acids differences are distant from the receptor binding site. Thus, receptor sub-types may exist but they may not be important from a functional or therapeutic standpoint.

MOTILIN-LIKE DRUGS (Table 52.1)

Erythromycin – The antibiotic properties of erythromycin and other macrolides were discovered in the early 1950’s. Since that time, erythromycin has been widely used in treating patients with gram-positive and gram-negative bacterial and mycoplasmal infections. Physicians and veterinarians noted that erythromycin therapy was accompanied by frequent gastrointestinal side effects including nausea and vomiting. This occurrence suggested to researchers that erythromycin might have effects on gastrointestinal motility. It was subsequently demonstrated that microbially-effective doses of erythromycin stimulate retrograde peristalsis and vomiting in dogs, and that lower microbially-ineffective doses of erythromycin stimulate migrating motility complexes and antegrade peristalsis similar to that induced by the endogenous gastrointestinal hormone, motilin.32,33,34
Gastroesophageal Sphincter Disorders
Motilin, erythromycin, and erythromycin analogues (e.g., LY-267108) increase gastroesophageal sphincter pressure in cats and dogs.35 Erythromycin also increases gastroesophageal sphincter pressure in cats in which the basal pressure has been lowered experimentally by esophageal acid perfusion or following intravenous isoproterenol administration.35 These studies suggest that erythromycin should be useful in treating cats, and perhaps dogs, wth gastroesophageal reflux and reflux esophagitis.
Gastric Emptying Disorders
Erythromycin accelerates gastric emptying by inducing antral contractions similar to phase III of the interdigestive state.36-39 The strong contractions associated with phase III normally occur only during the fasted state when they clear the stomach of large indigestible solids. After meals, intravenous or oral erythromycin accelerates gastric emptying of solid meals in dogs. EM574 is 250 times more potent than erythromycin in inducing phase III contractions in dogs and it has no anti-bacterial activity.37,38 EM574 is as effective as cisapride in normalizing gastric contractility and emptying in dogs with clonidine-induced gastroparesis in dogs.37,38

Colonic Motility Disorders
Erythromycin accelerates regional colonic transit in the dog.40 Erythromycin has been shown to stimulate canine but not feline colonic smooth muscle contraction in vitro.41 These results suggest that erythyromycin may be useful in the treatment of canine colonic motility disorders.

ACETYLCHOLINESTERASE INHIBITORS AND CHOLINOMIMETIC AGENTS (Table 52.1)

Ranitidine and Nizatidine – Ranitidine and nizatidine, classic histamine H2 receptor antagonists, stimulate gastrointestinal motility by inhibiting acetylcholinesterase activity.42-44 As parasympathetic potentiating agents, ranitidine and nizatidine stimulate gastric emptying and small intestinal and colonic motility. The prokinetic effects of ranitidine and nizatidine appear to be more prominent in the proximal gastrointestinal tract (i.e., gastric emptying). Other members of this classification, e.g., cimetidine and famotidine, apparently have no effect on gastrointestinal motility.

Bethanechol – Bethanechol is a cholinomimetic agent that binds muscarinic cholinergic receptors and stimulates motility throughout the gastrointestinal tract.

Esophageal Motility Disorders
Smooth muscle prokinetic agents, e.g., cisapride and metoclopramide, have limited clinical application in the treatment of canine idiopathic megaesophagus. Cisapride and metoclopramide stimulate distal esophageal peristalsis in those animal species (e.g., cat, human being, guinea pig) in which the distal esophageal muscularis is composed of smooth muscle. The domestic dog has evolved with a purely striated muscle esophageal muscularis which has a different regulation and therapeutic responsiveness.13 Bethanechol has been shown to stimulate esophageal propagating contractions in some dogs affected with idiopathic megaesophagus and is therefore a more appropriate prokinetic agent for the therapy of this disorder.45

Gastric Emptying Disorders
Ranitidine and nizatidine stimulate gastric antral contractions at gastric anti-secretory dosages (ranitidine 1.0-2.0 mg/kg PO BID; nizatidine 2.5-5.0 mg/kg PO BID) and may be useful as gastric prokinetic agents in dogs and cats.43,44,46

Colonic Motility Disorders
Infusions of ranitidine at doses of 3.0 mg/kg induce canine colonic propagating contractions in vivo.46 Ranitidine and nizatidine have also been shown to stimulate feline colonic smooth muscle contraction in vitro.47 These data suggest that ranitidine and nizatidine may be useful in the treatment of feline or canine colonic motility disorders.42

NITRIC OXIDE DONORS (Table 52.1, Figure 52.5)
Delayed gastric emptying is recognized as an important cause of upper gastrointestinal tract pathology (e.g., anorexia and vomiting) in companion animals.14 Delayed gastric emptying has been reported in infectious and inflammatory gastric diseases, diabetes mellitus, and radiation injury in the dog.48,49 Delayed gastric emptying has also been associated with several secondary conditions, including electrolyte disturbances (e.g., hypokalemia, hypocalcemia), metabolic disorders (e.g., hypoadrenocorticism, hypergastrinemia, uremia), concurrent drug usage (e.g., cholinergic antagonists, -adrenergic agonists, opiates), acute stress (e.g., sympathetic stimulation, spinal cord injury), and acute abdominal inflammation.48,49

Diabetes mellitus is the most common endocrinopathy of the domestic dog.50 Long-standing un-diagnosed or un-treated diabetes mellitus is associated with significant gastroparesis in the dog,51,52 just as it in humans. The pathogenesis of gastroparesis in diabetes mellitus is complex and probably multi-factorial, involving one or more of the cellular elements (neurons, smooth muscle cells, interstitial cells of Cajal) regulating gastric motility.53 An important pathophysiologic mechanism appears to be the loss of neuronal nitric oxide synthase, the enzyme responsible for the production of nitric oxide, an inhibitory neurotransmitter that is required for relaxation of smooth muscle and therefore a critical component of normal gastrointestinal motility. In the absence of nitric oxide, the stomach cannot relax, resulting in bloating, satiety, nausea, and vomiting.54

Cisapride, metoclopramide, and erythromycin have all been used with variable effect in diabetic gastroparesis. Therapy aimed instead at restoring nitrergic neurotransmission could have intrinsic beneficial effects in canine diabetic gastroparesis. AMU-301, a nitric oxide (NO) donor, is recognized as an effective treatment for diabetic gastroparesis in streptozotocin-induced (STZ) diabetic rat models of delayed gastric emptying,55 and may eventually prove useful in spontaneous canine diabetes mellitus.

PROSTAGLANDIN E1 ANALOGUES
Misoprostol is a prostaglandin E1 analogue that reduces the incidence of nonsteroidal anti-inflammatory drug-induced gastric injury. The main side effects of misoprostol therapy are abdominal discomfort, cramping, and diarrhea. Dog studies suggest that prostaglandins may initiate a giant migrating complex pattern and increase colonic propulsive activity.56 In vitro studies of misoprostol show that it stimulates feline and canine colonic smooth muscle contraction.57 Given its limited toxicity, misoprostol may be useful in dogs and cats with severe refractory constipation.

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33. Itoh Z, Suzuki T, Nakaya M, et al: Gastrointestinal motor-stimulationg activity of macrolide antibiotics and analysis of their side effects on the canine gut. Antimicrob Agents Chemother 26(6): 863-869, 1984
34. Sarna S, Gonzalez A, Ryan R. Enteric locus of action of prokinetics: ABT-229, motilin, and erythromycin. Amer J Physiol 278: G744-G752, 2000.
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38. Tanaka T, Mizumoto A, Mochiki E, et al. Effect of EM574 on postprandial pancreaticobiliary secretion, gastric motor activity, and emptying in conscious dogs. Dig Dis Sci 44: 1100-1106, 1999.
39. Tsukamoto K, Tagi Y, Nakazawa T, et al. Gastroprokinetic effect and mechanism of SK-896, a new motilin analogue, during the interdigestive period in conscious dogs. Pharmacology 63: 95-102, 2001.
40. Chiba T, Thomforde GM, Kost LJ, et al. Motilides accelerate regional gastrointestinal transit in the dog. Aliment Pharmacol Ther 14: 955-960, 2000.
41. Melgarejo LT, Simon DA, Washabau RJ. Erythromycin stimlulates canine, but not feline, longitudinal colonic muscle contraction. J Vet Intern Med 15: 333, 2001.
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Table 52-1. Mechanisms, sites of activity, indications, and doses of currently available gastrointestinal prokinetic agents.

Drug Classification/Mechanism Sites of Activity Indications Dose Other Properties

Dopaminergic D2 antagonist Drugs
Metoclopramide GES, stomach, intestine, Vomiting disorders, 0.2-0.5 mg/kg PO, IV TID; 2-adrenergic antagonist
CRTZ gastroesophageal reflux, 0.01-0.02 mg/kg/hr infusion 2-adrenergic antagonist
delayed gastric emptying, 5-HT4-serotonergic agonist
ileus/pseudo-obstruction 5-HT3-serotonergic antagonist

Domperidone GES, CRTZ Vomiting disorders, 0.05-0.10 mg/kg PO BID 2-adrenergic antagonist
gastroesophageal reflux 2-adrenergic antagonist

Sertonergic 5-HT4 agonist Drugs
Cisapride GES, stomach, intestine, Gastroesophageal reflux, 0.1-0.5 mg/kg PO TID 5-HT3-serotonergic antagonist
colon, CRTZ delayed gastric emptying, (doses as high as 5-HT1-serotonergic antagonist
ileus/pseudo-obstruction, as 0.5-1.0 mg/kg have 5-HT2-serotonergic agonist
constipation, chemotherapy- been used in some dogs)
induced vomiting

Mosapride Stomach Delayed gastric emptying 0.25-1.0 mg/kg PO BID None

Prucalopride Stomach, colon Delayed gastric emptying, 0.01-0.20 mg/kg PO BID None
constipation

Tegaserod Intestine, colon Constipation, 0.05-0.10 mg/kg PO or IV, BID 5-HT1-serotonergic antagonist
ileus/pseudo-obstruction

Motilin-like Drugs
Erythromycin GES, stomach, Gastroesophageal reflux, 0.5-1.0 mg/kg PO IV TID 5-HT3-serotonergic antagonist
intestine, colon delayed gastric emptying,
constipation (dogs)

Acetylcholinesterase Inhibitors and Cholinomimetic Agents
Ranitidine Stomach, colon Delayed gastric emptying, 1.0-2.0 mg/kg PO BID-TID H2 histaminergic antagonist
constipation

Nizatidine Stomach, colon Delayed gastric emptying, 2.5-5.0 mg/kg PO SID H2 histaminergic antagonist
constipation

Bethanechol Esophagus Canine idiopathic megaesophagus Dog: 5-15 mg/dog PO TID

Nitric Oxide Donors
AMU-301 Stomach Diabetic gastroparesis Not yet established
Prostanoids
Misoprostol Colon Constipation Dog: 2-5 g/kg PO TID-QID

Canine Inflammatory Bowel Disease: Pathogenesis, Diagnosis, Therapy

Definition of IBD – Inflammatory bowel disease (IBD) may be defined using clinical, pathogenetic, imaging, histologic, immunologic, pathophysiologic, and genetic criteria.

Clinical Criteria
IBD has been defined clinically as a spectrum of gastrointestinal disorders associated with chronic inflammation of the stomach, intestine and/or colon of unknown etiology. A clinical diagnosis of IBD is considered only if affected animals have: (1) persistent (>3 weeks in duration) gastrointestinal signs (anorexia, vomiting, weight loss, diarrhea, hematochezia, mucousy feces), (2) failure to respond to symptomatic therapies (parasiticides, antibiotics, gastrointestinal protectants) alone, (3) failure to document other causes of gastroenterocolitis by thorough diagnostic evaluation, and (4) histologic diagnosis of benign intestinal inflammation. Small bowel and large bowel forms of IBD have been reported in both dogs and cats, although large bowel IBD appears to be more prevalent in the dog.
Pathogenetic Criteria

Known causes of intestinal diarrhea should first be considered: food sensitivity reaction, bacterial infection, parasitic infection, fungal infection, pancreatic insufficiency, intestinal neoplasia, lymphangiectasia (canine), and hyperthyroidism (feline).

Most current hypotheses on the pathogenesis of IBD hold that the gut has sustained reactivity to endogenous bacterial and/or food antigens.

Histologic Criteria
IBD has been defined histologically by the type of inflammatory infiltrate (neutrophilic, eosinophilic, lymphocytic, plasmacytic, granulomatous), associated mucosal pathology (villus atrophy, fusion, crypt collapse), distribution of the lesion (focal or generalized, superficial or deep), severity (mild, moderate, severe), mucosal thickness (mild, moderate, severe), and topography (gastric fundus, gastric antrum, duodenum, jejunum, ileum, cecum, ascending colon, descending colon). As with large intestinal IBD, subjective interpretation of small intestinal IBD lesions has made it difficult to compare tissue findings between pathologists. Subjectivity in histologic assessments has led to the development of several IBD grading systems.

Immunologic Criteria
IBD has been defined immunologically by the innate and adaptive response of the mucosa to gastrointestinal antigens. Although the precise immunologic events of canine and feline IBD remain to be determined, a prevailing hypothesis for the development of IBD is the loss of immunologic tolerance to the normal bacterial flora or food antigens, leading to abnormal T cell immune reactivity in the gut microenvironment. Genetically engineered animal models (e.g., IL-2, IL-10, and T cell receptor knockouts) that develop IBD involve alterations in T cell development and/or function suggesting that T cell populations are responsible for the homeostatic regulation of mucosal immune responses. Immunohistochemical studies of canine IBD have demonstrated an increase in the T cell population of the lamina propria, including CD3+ cells and CD4+ cells, as well as macrophages, neutrophils, and IgA-containing plasma cells. Many of the immunologic features of canine IBD can be explained as an indirect consequence of mucosal T cell activation. Enterocytes are also likely involved in the immunopathogenesis of IBD. Enterocytes are capable of behaving as antigen-presenting cells, and interleukins (e.g., IL-7 and IL-15) produced by enterocytes during acute inflammation activate mucosal lymphocytes. Up-regulation of Toll-like receptor 4 (TLR4) and Toll-like receptor 2 (TLR2) expression contribute to the innate immune response of the colon. Thus, the pathogenesis and pathophysiology of IBD appears to involve the activation of a subset of CD4+ T cells within the intestinal epithelium that overproduce inflammatory cytokines with concomitant loss of a subset of CD4+ T cells, and their associated cytokines, which normally regulate the inflammatory response and protect the gut from injury. Enterocytes, behaving as antigen-presenting cells, contribute to the pathogenesis of this disease.

Pathophysiologic Criteria
IBD may be defined pathophysiologically in terms of changes in transport, blood flow, and motility. The clinical signs of IBD, whether small or large bowel, have long been attributed to the pathophysiology of malabsorption and hypersecretion, but experimental models of canine IBD have instead related clinical signs to the emergence of abnormality motility patterns. The pathophysiology of small intestinal IBD is explained by at least two interdependent mechanisms: the mucosal immune response, and accompanying changes in motility.

Immune Responses
A generic inflammatory response involving cellular elements (B and T lymphocytes, plasma cells, macrophages, and dendritic cells), secretomotor neurons (e.g., VIP, substance P, and cholinergic neurons), cytokines and interleukins, and inflammatory mediators (e.g., leukotrienes, prostanoids, reactive oxygen metabolites, nitric oxide, 5-HT, IFN-γ, TNF-α, and platelet-activating factor) is typical of canine and feline inflammatory bowel disease. There are many similarities between the inflammatory response of the small and large intestine, but recent immunologic studies suggest that IBD of the canine small intestine is a mixed Th1/Th2 response whereas IBD of the canine colon may be more of a Th1 type response with elaboration of IL-2, IL-12, INF-γ, and TNF-.

Motility Changes
Experimental studies of canine small (and large) intestinal IBD have shown that many of the clinical signs are related to motor abnormalities of the gastrointestinal tract. Ethanol and acetic acid perfusion of the canine ileum or colon induces a form of IBD syndrome indistinguishable from the natural condition. Inflammation in this model suppresses the normal phasic contractions of the colon, including the migrating motility complex, and triggers the emergence of giant migrating contractions (GMCs). The appearance of these GMCs in association with inflammation is a major factor in producing diarrhea, abdominal cramping, and urgency of defecation. GMCs are powerful lumen-occluding contractions that rapidly propel pancreatic, biliary, and intestinal secretions in the fasting state, and undigested food in the fed state, to the colon to increase its osmotic load. Malabsorption results from direct injury to the epithelial cells and from ultrarapid propulsion of intestinal contents by giant migrating contractions (GMCs) so that sufficient mucosal contact time is not allowed for digestion and absorption to take place.

Inflammation impairs the regulation of the colonic motility patterns at several levels, i.e., enteric neurons, interstitial cells of Cajal, and circular smooth muscle cells. Inflammation-induced changes in the amplitude and duration of the smooth muscle slow wave plateau potentials contribute to the suppression of rhythmic phasic contractions (RPCs). These alterations likely have their origin in structural as well as functional damage to the interstitial cells of Cajal. At the same time that inflammation suppresses the (RPCs), inflammation sensitizes the colon to the stimulation of GMCs by the neurotransmitter substance P. These findings suggest that SP increases the frequency of GMCs during inflammation, and that selective inhibition of GMCs during inflammation may minimize the symptoms of diarrhea, abdominal discomfort, and urgency of defecation associated with these contractions.

Inflammation suppresses the generation of tone and phasic contractions in the circular smooth muscle cells through multiple molecular mechanisms. Inflammation shifts muscarinic receptor expression in circular smooth muscles from the M3 to the M2 subtype. This shift has the effect of reducing the overall contractility of the smooth muscle cell. Inflammation also impairs calcium influx and down-regulates the expression of the L-type calcium channel, which may be important in suppressing phasic contractions and tone while concurrently stimulating GMCs in the inflamed colon. Changes in the open-state probability of the large conductance calcium-activated potassium channels (KCa) partially attenuate this effect. Inflammation also modifies the signal transduction pathways of circular smooth muscle cells. Phospholipase A2 and protein kinase C (PKC) expression and activation are significantly altered by colonic inflammation and this may partially account for the suppression of tone and phasic contractions. PKC , β, and  isoenzyme expression is down-regulated, PKC  and  isoenzyme expression is up-regulated, and the cytosol-to-membrane translocation of PKC is impaired. The L-type calcium channel, already reduced in its expression, is one of the molecular targets of PKC. Inflammation also activates the transcription factor NF-B which further suppresses cell contractility.

Genetic Criteria
IBD may be defined by genetic criteria in several animal species. Crohn’s disease and ulcerative colitis are more common in certain human genotypes, and a mutation in the NOD2 gene (nucleotide-binding oligomerization domain2) has been found in a sub-group of patients with Crohn’s disease. Genetic influences have not yet been identified in canine or feline IBD, but certain breeds (e.g., German shepherds, Boxers) appear to be at increased risk for the disease.

Overview of Pathophysiology of IBD: Inflammation impairs motility by inducing changes in receptor, signal transduction, and ion channel activity in smooth muscle cells and enteric neurons. Changes include but not are limited to a shift in muscarinic receptor expression from M3 to M2 receptor subtype, impaired calcium mobilization, down-regulation of L-type calcium channel expression, changes in the open-state probability of the large conductance calcium-activated potassium channels (KCa), down-regulation of phospholipase A2 and protein kinase C , β, and  isoenzymes, and activation of the transcription factor NF-B in smooth muscle cells. Inflammation also sensitizes the colon to the stimulation of GMCs by the neurotransmitter substance P. PKC = protein kinase C, PLA2 = Phospholipase A2 , M = muscarinic, NF-B = Nuclear factor-B, KCa = Calcium-activated potassium channel, SP = substance P, ACh = acetylcholine.

Clinical Examination
The clinical signs of large intestinal IBD are those of a large bowel-type diarrhea, i.e., marked increased frequency, reduced fecal volume per defecation, blood pigments and mucous in feces, and tenesmus. Anorexia, weight loss, and vomiting are occasionally reported in animals with severe IBD of the colon or concurrent IBD of the stomach and/or small intestine. Clinical signs usually wax and wane in their severity. A transient response to symptomatic therapy may occur during the initial stages of IBD. As the condition progresses, diarrhea gradually increases in its frequency and intensity, and may become continuous. In some cases the first bowel movement of the day may be normal or nearly normal, whereas successive bowel movements are reduced in volume and progressively more urgent and painful. During severe episodes, mild fever, depression, and anorexia may occur.

There does not appear to be any sex predilection, but age may be a risk factor with IBD appearing more frequently in middle aged animals (mean age approximately 6 years with a range of 6 months to 20 years). German shepherd and Boxer dogs are at increased risk for IBD, and pure-breed cats appear to be at greater risk. Cats more often present with an upper gastrointestinal form of IBD, whereas dogs are at risk for both small and large bowel IBD.

Physical examination is unremarkable in most cases. Thickened bowel loops may be detected during abdominal palpation if the small bowel is concurrently involved. Digital examination of the anorecturm may evoke pain or reveal irregular mucosa, and blood pigments and mucous may be evident on the exam glove.

Diagnosis

Complete blood counts, serum chemistries, and urinalyses are often normal in mild cases of large bowel IBD. Chronic cases may have one or more subtle abnormalities. One review of canine and feline IBD reported several hematologic abnormalities including mild anemia, leukocytosis, neutrophilia with and without a left shift, eosinophilia, eosinopenia, lymphocytopenia, monocytosis, and basophilia. The same study reported several biochemical abnormalities including increased activities of serum alanine aminotransferase and alkaline phosphatase, hypoalbuminemia, hypoproteinemia, hyperamylasemia, hyperglobulinemia, hypokalemia, hypocholesterolemia, and hyperglycemia. No consistent abnormality in the complete blood count or serum chemistry has been identified.

A scoring index for disease activity in canine IBD was recently developed that relates severity of clinical signs to serum acute-phase protein (C-reactive protein, serum amyloid A) concentrations. The canine IBD activity index (CIBDAI) assigns levels of severity to each of several gastroenterologic signs (e.g., anorexia, vomiting, weight loss, diarrhea), and it appears to be a reliable index of mucosal inflammation in canine IBD. Interestingly, both the activity index and serum concentrations of C-reactive protein (CRP) improve with successful treatment, suggesting that serum CRP is suitable for the laboratory evaluation of therapy in canine IBD. Other acute-phase proteins were less specific than CRP. One important caveat that should be emphasized is that altered CRP is not prima facie evidence of gastrointestinal inflammation. Concurrent infections or other inflammatory conditions could cause an acute-phase response, including CRP, in affected patients.

Treatment – Management of IBD consists of 1) dietary therapy, 2) exercise, 3) antibiotics, 4) probiotics, 5) anti-diarrheal agents, 6) restoration of normal motility, 7) anti-inflammatory or immunosuppressive therapy, and 8) behavioral modification.

1. Dietary Therapy

The precise immunologic mechanisms of canine and feline IBD have not yet been determined, but a prevailing hypothesis for the development of IBD is the loss of immunologic tolerance to the normal bacterial flora or food antigens. Accordingly, dietary modification may prove useful in the management of canine and feline IBD. Several nutritional strategies have been proposed including novel proteins, hydrolyzed diets, anti-oxidant diets, medium chain triglyceride supplementation, low fat diets, modifications in the omega-6/omega-3 (-6/-3) fatty acid ratio, and fiber supplementation. Of these strategies, some evidence-based medicine has emerged for the use of novel protein, hydrolyzed, and fiber-supplemented diets.

Food sensitivity reactions were suspected or documented in 49% of cats presented because of gastroenterologic problems (with or without concurrent dermatologic problems) in a prospective study of adverse food reactions in cats. Beef, wheat, and corn gluten were the primary ingredients responsible for food sensitivity reactions in that study, and most of the cats responded to the feeding of a chicken- or venison-based selected-protein diet for a minimum of 4 weeks. The authors concluded that adverse reactions to dietary staples are common in cats with chronic gastrointestinal problems and that they can be successfully managed by feeded selected-protein diets. Further support for this concept comes from studies in which gastroenterologic or dermatologic clinical signs were significantly improved by the feeding of novel proteins.

Evidence is accruing that hydrolyzed diets may be useful in the nutritional management of canine IBD. The conceptual basis of the hydrolyzed diet is that oligopeptides are of insufficient size and structure to induce antigen recognition or presentation. In one preliminary study, dogs with inflammatory bowel disease showed significant improvement following the feeding of a hydrolyzed diet although they had failed to respond to the feeding of a novel protein. Clinical improvement could not be solely attributed to the hydrolyzed nature of the protein source because the test diet had other modified features, i.e., high digestibility, cornstarch rather than intact grains, medium chain triglycerides, and an altered ratio of -6 to -3 polyunsaturated fatty acids. Additional studies will be required to ascertain the efficacy of this nutritional strategy in the management of IBD.

Fiber-supplemented diets may be useful in the management of irritable bowel syndrome (IBS) in the dog. IBS is a poorly defined syndrome in the dog that may or may not bear resemblance to IBS in humans. Canine IBS has been defined as a chronic large-bowel type diarrhea without known cause and without evidence of colonic inflammation on colonoscopy or biopsy. Dogs fulfilling these criteria were successfully managed with soluble fiber (psyllium hydrophilic mucilloid) supplementation of a highly digestible diet.

2. Exercise

Experimental IBD in the dog is accompanied by significant abnormalities in the normal colonic motility patterns. Physical exercise has been shown to disrupt the colonic MMCs and to increase the total duration of contractions that are organized as non-migrating motor complexes during the fed state. Exercise also induces GMCs, defecation, and mass movement in both the fasted and fed states. The increased motor activity of the colon and extra GMCs that result from physical exercise may aid in normal colonic motor function.

3. Antibiotics

Some IBD cases are initiated by true enteric pathogens, while others are complicated by small intestinal bacterial overgrowth. Some IBD cases may show short term responsiveness to one or more antibiotics, e.g., tylosin, metronidazole, or oxytetracycline.

4. Probiotics

Probiotics are living organisms with low or no pathogenicity that exert beneficial effects (e.g., stimulation of innate and acquired immunity) on the health of the host. The Gram-positive commensal lactic acid bacteria (e.g., Lactobacilli) have many beneficial health effects, including enhanced lymphocyte proliferation, innate and acquired immunity, and anti-inflammatory cytokine production. Lactobacillus rhamnosus GG, a bacterium used in the production of yogurt, is effective in preventing and treating diarrhea, recurrent Clostridia difficile infection, primary rotavirus infection, and atopic dermatitis in humans. Lactobacillus rhamnosus GG has been safely colonized in the canine gastrointestinal tract, although probiotic effects in the canine intestine have not been firmly established. The probiotic organism, Enterococcus faecium (SF68), has been safely colonized in the canine gastrointestinal tract, and it has been shown to increase fecal IgA content and circulating mature B (CD21+/MHC class II+) cells in young puppies. It has been suggested that this probiotic may be useful in the prevention or treatment of canine gastrointestinal disease. This organism may, however, enhance Campylobacter jejuni adhesion and colonization of the dog intestine, perhaps conferring carrier status on colonized dogs.

Two recent studies have shown that many commercial veterinary probiotic preparations are not accurately represented by label claims. Quality control appears to be deficient for many of these formulations. Until these products are more tightly regulated, veterinarians should probably view product claims with some skepticism.

5. Anti-Diarrheal Agents

Prostaglandin Synthetase Inhibitors
– Sulfasalazine – 10-25 mg/kg TID-QID, PO
– 5-aminosalicylate – 5-10 mg/kg PO, TID-QID (dog)

μ,δ-Opioid Agonists – These drugs stimulate circular smooth muscle contraction and, therefore,intestinal segmentation. It has been shown more recently that these drugs also stimulate absorption, and inhibit secretion of, fluid and electrolytes.
– Loperamide 0.08 mg/kg TID, PO-preferred drug
– Diphenoxylate 0.05-0.10 mg/kg TID-QID, PO-available in Lomotil

5-HT3 Serotonin Antagonists – Antagonists of the neuronal 5-HT3 receptor inhibit Cl- and H2O secretion from intestinal epithelial cells.
– Ondansetron (Zofran, Glaxo) – 0.5-1.0 mg/kg BID, PO
– Granisetron (Kytril, SmithKline Beecham) – 0.5-1.0 mg/kg BID, PO

α2-Adrenergic Antagonists – These drugs must be used carefully as they can activate α2-adrenergic receptors in the chemoreceptor trigger zone and cause vomiting.
– Clonidine 5-10 μg/kg BID-TID, SQ/PO

6. Restoration of Normal Motility

The mixed ,-opioid agonist, loperamide, stimulates colonic fluid and electrolyte absorption while inhibiting colonic propulsive motility. Loperamide (0.08 mg/kg PO TID-QID) may be beneficial in the treatment of difficult or refractory cases of large bowel-type IBD.

7. Anti-Inflammatory/Immunosuppressive Therapy

Sulfasalazine – Sulfasalazine is a highly effective prostaglandin synthetase inhibitor that has proven efficacy in the therapy of large bowel IBD in the dog. Sulfasalazine is a compound molecule of 5-aminosalicylate (meselamine) and sulfapyridine linked in an azo chemical bond. Following oral dosing, most of the sulfasalazine is transported to the distal gastrointestinal tract where cecal and colonic bacteria metabolize the drug to its component parts. Sulfapyridine is largely absorbed by the colonic mucosa but much of the 5-aminosalicylate remains in the colonic lumen where it inhibits mucosal lipoxygenase and the inflammatory cascade. Sulfasalazine has been recommended for the treatment of canine large bowel IBD at doses of 10-25 mg/kg PO TID for 4-6 weeks. With resolution of clinical signs, sulfasalazine dosages are gradually decreased by 25 per cent at 2-week intervals and eventually discontinued while maintaining dietary management. Salicylates are readily absorbed and induce toxicity in cats, therefore this drug classification should be used with great caution in cats. If used in cats, some authors have recommended using half of the recommended dog dose (i.e., 5-12.5 mg/kg PO TID. Sulfasalazine usage has been associated with the development of keratoconjunctivitis sicca in the dog, so tear production should be assessed subjectively (by the pet owner) and objectively (by the veterinarian) during usage.

Other 5-Aminosalicylates – This drug classification was developed to reduce the toxicity of the sulfapyridine portion of the parent molecule (sulfasalazine) and to enhance the efficacy of the 5-aminosalicylate portion. Meselamine (Dipentum, Asachol) and dimeselamine (Olsalazine) are available for use in the treatment of canine large bowel IBD. Olsalazine has been used at a dosage of 5-10 mg/kg PO TID in the dog. Despite the formulation of sulfa-free 5-aminosalicylate preparations, instances of keratoconjunctivitis sicca have still been reported in the dog.

Metronidazole – Metronidazole (10-20 mg/kg PO BID-TID) has been used in the treatment of mild to moderate cases of large bowel IBD in both dogs and cats. Metronidazole has been used either as a single agent or in conjunction with 5-aminosalicylates or glucocorticoids. Metronidazole is believed to have several beneficial properties, including anti-bacterial, anti-protozoal, and immunomodulatory effects. Side effects include anorexia, hypersalivation, and vomiting at recommended doses and neurotoxicity (ataxia, nystagmus, head title, and seizures) at higher doses. Side effects usually resolve with discontinuation of therapy but diazepam may accelerate recovery of individual patients.

Glucocorticoids – Anti-inflammatory doses of prednisone or prednisolone (1-2 mg/kg PO SID) may be used to treat IBD in dogs that have failed to respond to dietary management, sulfasalazine, or metronidazole, and as adjunctive therapy to dietary modification in feline IBD. Prednisone or prednisolone is used most frequently, as both have short durations of action, are cost-effective, and are widely available. Equipotent doses of dexamethasone are equally effective but may have more deleterious effects on brush border enzyme activity. Prednisone should be used for 2-4 weeks depending upon the severity of the clinical signs. Higher doses of prednisone (e.g., 2-4 mg/kg PO SID) may be needed to control severe forms of eosinophilic colitis or hypereosinophilic syndrome in cats. Combination therapy with sulfasalazine, metronidazole, or azothioprine may reduce the overall dosage of prednisone needed to achieve remission of clinical signs. As with sulfasalazine, the dose of glucocorticoid may be reduced by 25% at 1-2 week intervals while hopefully maintaining remission with dietary modification.

Because of steroid side effects and suppression of the hypothalamic-pituitary-adrenal axis, several alternative glucocorticoids have been developed that have excellent topical (i.e., mucosal) anti-inflammatory activity but are significantly metabolized during first pass hepatic metabolism. Budesonide has been used for many years as an inhaled medication for asthma, and an enteric-coated form of the drug is now available for treatment of IBD in humans (and animals). There is little evidence-based medicine in support of the use of this medication in canine or feline IBD, but doses of 1 mg/cat or 1 mg/dog per day have been used with some success in anecdotal cases.

Azathioprine – Azathioprine is a purine analog that, following DNA incorporation, inhibits lymphocyte activation and proliferation. It is rarely effective as a single agent, and it should instead be used as adjunctive therapy with glucocorticoids. Azathioprine may have a significant steroid-sparing effect in IBD. Doses of 2 mg/kg PO q 24 hours in dogs and 0.3 mg/kg PO q 48 hours in cats have been used with some success in IBD. It may take several weeks or months of therapy for azathioprine to become maximally effective. Cats particularly should be monitored for side effects, including myelosuppression, hepatic disease, and acute pancreatic necrosis.

Cyclosporine – Cyclosporine has been used in the renal transplantation patient for its inhibitory effect on T cell function. In more recent times, cyclosporine has been used in a number of immune-mediated disorders, including keratoconjunctivitis sicca, perianal fistula (anal furunculosis), and IMHA. Anecdotal reports suggest that cyclosporine (3-7 mg/kg PO BID) may be useful in the treatment of some cases of refractory IBD. Evidence-based medicine studies will be needed to establish efficacy, but anecdotal experience would suggest that cyclosporine may be useful in some of the more difficult or refractory cases of IBD.

Chlorambucil – Chlorambucil (2 mg/m2 PO every other day) has been used in place of azathioprine in some difficult or refractory cases of feline IBD.

8. Behavioral Modification
Inflammatory bowel disease and irritable bowel syndrome very likely have underlying behavioral components. Abnormal personality traits and potential environmental stress factors were identified in 38% of dogs in one study. Multiple factors were present in affected households, including travel, re-location, house construction, separation anxiety, submissive urination, noise sensitivity, and aggression.185 The role of behavior in the pathogenesis and therapy of canine and feline gastrointestinal disorders remains largely unexplored.

Prognosis
Most reports indicate that the short-term prognosis for control of IBD is good to excellent. Following completion of drug therapy, many animals are able to maintain remission of signs with dietary management alone. Treatment failures are uncommon and are usually due to 1) incorrect diagnosis (it is especially important to rule out alimentary lymphosarcoma), 2) presence of severe disease such as histiocytic ulcerative colitis and protein-losing enteropathy or irreversible mucosa lesions such as fibrosis, 3) poor client compliance with appropriate drug/dietary recommendations, 4) use of inappropriate drugs or nutritional therapy, and 5) presence of concurrent disease such as small intestinal bacterial overgrowth or hepatobiliary disease. The prognosis for cure of IBD is poor, and relapses should be anticipated.

References

A more detailed review of diseases of the intestine, including 294 refereences, may be found in: Washabau RJ. Diseases of the Intestine. In, Textbook of Veterinary Internal Medicine, 6th edition, Ettinger SJ and Feldman EC, editors. WB Saunders Co, Philadelphia, PA, 2005: 1378-1408.

Feline Hepatobiliary Disease: What’s New in Diagnosis and Therapy?

Toxic Hepatopathy

Pathogenesis and Etiology – Toxic hepatopathy is a direct injury to hepatocytes or other cells in the liver attributable to therapeutic agents or environmental toxins. Cats are particularly sensitive to phenolic toxicity because of limited hepatic glucuronide transferase activity. The discriminatory eating habits of cats may account for the relatively uncommon occurrence of hepatotoxicity from ingested environmental toxins such as pesticides, household products, and other chemicals. Medical therapies (acetaminophen, acetylsalicylic acid, megesterol, ketoconazole, phenazopyridine, tetracycline, diazepam, griseofulvin) and environmental toxins (pine oil + isopropanol, inorganic arsenicals, thallium, zinc phosphide, white phosphorus, Amanita phalloides, aflatoxin, phenols) may contribute to liver pathology. A severe idiosyncratic hepatotoxicity has been reported with diazepam administration in several groups of cats. Clinical signs in affected cats include anorexia, vomiting, weight loss, ascites, encephalopathy, and death. The histology is characterized by severe central lobular necrosis and mild vacuolation.

Mechanisms of Hepatotoxicity – The liver is an important site of drug toxicity and oxidative stress because of its proximity and relationship to the gastrointestinal tract. Seventy-five to 80% of hepatic blood flow comes directly from the gastrointestinal tract and spleen via the main portal vein. Portal blood flow transports nutrients, bacteria and bacterial antigens, drugs, and xenobiotic agents absorbed from the gut to the liver in more concentrated form. Drug-metabolizing enzymes detoxify many xenobiotics but activate the toxicity of others. Hepatic parenchymal and non-parenchymal cells may all contribute to the pathogenesis of hepatic toxicity. The major mechanisms of hepatotoxicity include: Bile Acid-Induced Hepatocyte Apoptosis, Cytochrome P4502E1-Dependent Toxicity , Peroxynitrite-induced Hepatocyte Toxicity, Adhesion Molecules and Oxidant Stress in Inflammatory Liver Injury, Microvesicular and Nonalcoholic Steatosis.

Diagnosis of Hepatotoxicity – Clinical evidence includes supportive history, normal liver size to mild generalized hepatomegaly, elevated serum liver enzyme activities (predominantly ALT and AST), hypoalbuminemia and hypocholesterolemia, and recovery or death depending upon severity and magnitude of exposure. There are no pathognomonic histologic changes in the liver, although necrosis with minimal inflammation and lipid accumulation are considered classic findings.

Treatment of Hepatotoxicity – Few hepatotoxins have specific antidotes, and recovery relies almost exclusively on symptomatic and supportive therapy. If recognized, acetaminophen toxicity may be treated with acetylcysteine (sulfhydryl group donor), ranitidine or cimetidine (cytochrome P450 enzyme inhibition), ascorbic acid (anti-oxidant), and androstanol (consititutive androstane receptor [CAR] inhibition).

Hepatic Lipidosis

Pathogenesis and Etiology – Feline hepatic lipidosis is now a well-recognized syndrome characterized by intracellular accumulation of lipid with clinicopathologic findings consistent with intrahepatic cholestasis. The precise incidence of the syndrome is unknown but pathology surveys have revealed 5% of animals affected with this lesion. While some cases result from diabetes mellitus, the majority of cases are felt to result from the nutritional and biochemical peculiarities of the cat. It has been suggested, for example, that the cat is not very capable of regulating intermediary metabolism during starvation. Although the biochemistry of this lesion has not been completely worked out, there are several biochemical and nutritional peculiarities that predispose the cat to this syndrome. Some of the known biochemical peculiarities of the cat are: essentiality of dietary arginine; low levels of hepatic ornithine; high dietary protein requirements; lack of hepatic enzymatic adaptation to low dietary levels of protein; relative insufficiency of intestinal pyrroline-5-carboxylate synthase activity; relative insufficiency of intestinal and hepatic glutamate reductase; relative insufficiency of intestinal ornithine transcarbamylase; peculiarities in lipoprotein metabolism; and, differences in orotic acid metabolism.

Clinical Features – Most studies suggest that there are no breed, sex, or age predilections. A recent retrospective study by Center and her colleagues suggests that female and middle-age cats are at greater risk for the illness. Obesity may be a predisposing factor, although the syndrome readily develops in fit animals. It has been suggested that obesity followed by a period of anorexia and weight loss are particularly at risk. Cats affected with this syndrome are often presented with a complaint of anorexia, often of several weeks duration. These cats are also commonly presented with jaundice. Other reported clinical signs include vomiting, weakness, weight loss, and diarrhea. Physical examination often reveals dehydration, cachexia, jaundice, and hepatomegaly. All of these findings are also reported in cats with acute pancreatitis and other hepatobiliary disease.

Diagnosis – Hyperechoic changes in the hepatic parenchyma at ultraonography have been cited as a pathognomonic finding, but these changes may be seen in other feline hepatic disorders. Diagnosis should be substantiated by aspiration cytology, or better still, tissue biopsy (percutaneous, trans-abdominal ultrasound guidance, laparoscopy, or open laparotomy). Aspiration cytology has weak sensitivity and specificity, and may miss other diagnoses.

Therapy – Nutritional support is the cornerstone of therapy of this disorder. Most studies suggest that enteral feeding (by “forced” or encouraged feeding, pharyngostomy, gastrostomy, or enterostomy feeding tube) of commercially available cat foods will effect recovery in 90-95% of affected animals. Biourge and his colleagues have characterized some of the metabolic changes that take place during fasting in obese cats. They have been particularly interested in the effects of protein, lipid, or carbohydrate supplementation on hepatic lipid accumulation during rapid weight loss in obese cats. They found that small amounts of protein administered to obese cats during fasting significantly reduced accumulation of lipids in the liver, prevented increases in alkaline phosphatase activity, eliminated negative nitrogen balance, and appeared to minimize muscle catabolism. Carbohydrate supplementation reduced hepatic lipid accumulation, but metabolic abnormalities still developed. Lipid supplementation alone did not ameliorate hepatic lipidosis and even resulted in more severe lipid accumulation than under conditions of fasting alone. The use of benzodiazepine agonists (e.g. diazepam, oxazepam, elfazepam) and 5-HT2 agonists (e.g., cyproheptadine) as appetite stimulants has been encouraged in anorexic cats. These compounds particularly the benzodiazepine agonists, should be used with caution as they may exacerbate pre-existing hepatic encephalopathy. Benzodiazepine agonists have been shown to worsen hepatoencephalopathy in other animal species through activation of the neuronal benzodiazepine/GABA receptor-chloride channel complex.

Feline Cholangitis
Pathogenesis and Etiology – This syndrome has been classified in three different ways:

University of Minnesota Classification (Doug Weisse; 1996) – Lymphocytic portal hepatitis and suppurative cholangitis. This classification system implies that there are two different inflammatory conditions involving the feline liver: inflammatory liver disease (lymphocytic portal hepatitis) and inflammatory biliary tract disease (suppurative cholangitis). Limitations of this classification system – It fails to recognize that acute (i.e., suppurative) cholangitis can progress to more chronic forms (i.e., lymphocytic) of the disease. This system also implies that there is suppuration, which, in fact, is rarely seen. Neutrophilic infiltrates do occur, but rarely does it progress to suppuration. Finally, it’s not entirely clear whether lymphocytic portal hepatitis is a distinct clinical entity or just a histologic lesion.

WSAVA International Liver Standardization Group Classification (Multi-Institutional Group; 2002) – Neutrophilic cholangitis, lymphocytic cholangitis, lymphocytic portal hepatitis. This classification system implies that there are acute (neutrophilic) and chronic (lymphocytic) forms of cholangitis, and that there may be a separate form of portal hepatitis in cats. Limitations of this classification system – We still don’t know if lymphocytic portal hepatitis is a disease or a histologic lesion.

Neutrophilic cholangitis – This disorder has been seen primarily in young to middle-aged male cats with clinical signs of acute vomiting, diarrhea, anorexia, and lethargy. Physical examination findings often reveal fever, icterus, abdominal pain, and hepatomegaly (<50% of cases). Laboratory findings frequently reveal mild to moderate leukocytosis with mild to moderate elevations in ALT, AST, GGT, and ALP. Based on recent studies, cats affected with this form of cholangitis often have related disease, e.g., pancreatitis and inflammatory bowel disease. The diagnosis of suppurative cholangiohepatitis is achieved by serum liver enzymology; ultrasonographic characterization of the liver parenchyma; culture – bile, gallbladder, cholelith, liver; Gram staining; and, biopsy of the liver and/or extrahepatic biliary system. Common bacterial isolates in affected cases include E. coli, Clostridia, Bacteroides, Actinomyces, α-Strep. The treatment of this syndrome has included appropriate antibiotic based on culture and sensitivity, cholelith removal where appropriate, bile duct decompression if necessary, fluid and electrolyte maintenance, and ursodeoxycholate therapy (10-15 mg/kg P.O. SID).

Lymphocytic cholangitis – Chronic lymphocytic cholangitis is characterized by a mixed inflammatory response (equal numbers of lymphocytes or plasma cells and neutrophils) within portal areas and bile ducts. Other features of chronicity include marked bile duct proliferation, bridging fibrosis, and pseudolobule formation. Chronic cholangiohepatitis may progress to progressive biliary cirrhosis and the death of the patient. Lymphocytic cholangitis may represent a persistent bacterial infection or an immune-mediated response may result in a chronic self-perpetuating disorder. Clinical signs are usually of a chronic, intermittent or persistent nature. With chronic cholangiohepatitis, a long-standing history over a period of weeks or months is more likely. Vomiting, icterus, hepatomegaly and ascites are common findings. Hepatic encephalopathy and excessive bleeding are uncommon unless severe end-stage liver disease is present. The best treatments for this syndrome are not clearly understood. It has been suggested that many cats require multi-component therapy, e.g., glucocorticoids – 1-2 mg/kg PO SID; metronidazole – 7.5 mg/kg PO BID; ursodeoxycholate 10-15 mg/kg PO SID; vitamin K1 – 1.5-5 mg Q 2-3 weeks; dietary manipulation for presumed I.B.D.; and, immune modulation with azathioprine or chlorambucil.

Lymphocytic portal hepatitis – A retrospective review of liver biopsies of cats with inflammatory liver disease identified a subset of cats with lymphocytic portal infiltrates which had histopathologic features distinct from cats with acute or chronic cholangitis. The term lymphocytic portal hepatitis has been proposed for this disorder. As opposed to findings in cholangitis, there is a lack of neutrophilic inflammation, bile duct involvement, infiltration of inflammatory cells into hepatic parenchyma, or periportal necrosis. Lymphocytic portal hepatitis is not associated with inflammatory bowel disease or pancreatitis. Previous reports of progressive lymphocytic cholangitis or lymphocytic cholangitis referred to varying degrees of neutrophilic inflammation and the condition may actually have been a chronic form of cholangitis. Lymphocytic portal hepatitis is a common finding in liver biopsies of older cats, suggesting that it is a common aging change or that a sub-clinical form of disease is prevalent. Lymphocytic portal hepatitis appears to progress slowly with varying degrees of portal fibrosis and bile duct proliferation but no pseudolobule formation. Concurrent hepatic lipidosis is less likely than with cholangitis.

Hepatic Neoplasia

Pathogenesis and Etiology – Primary neoplasms of the feline liver are uncommon. Cholangiocellular carcinoma and hepatocellular carcinoma are the most important of the primary feline liver neoplasms, but they are of very low incidence and therefore minor importance. Metatstatic liver neoplasia are much more important in cats. The most common metastatic tumors to the liver are lymphoma, systemic mast cell disease, hemangiosarcoma, and myeloproliferative disorders.

Clinical Features – Clinical signs are fairly non-specific, but may be similar to clinical signs reported in cats with other liver disorders, for example: lethargy, anorexia, weight loss, and intermittent vomiting. Abdominal effusion, jaundice, and encephalopathy may be seen terminally.

Diagnosis – Laboratory data are also usually non-specific. Elevations in serum liver enzyme activities and abnormalities in bile salt metabolism should be obvious, but they are not remarkably different from cats with other liver disorders. Imaging studies (radiography, ultrasonography) may provide evidence of diffuse hepatomegaly or of discrete tumors involving one or more liver lobes. Definitive diagnosis always requires aspiration cytology, or better yet, tissue biopsy. Aspirates and/or tissue biopsies may be obtained by percutaneous trans-abdominal ultrasound guidance, laparoscopy, or laparotomy techniques.

Therapy – The cell of origin of a metastatic tumor should always be identified, if possible. Chemo- or other therapies may then be selected based on a working knowledge of the biologic basis of the tumor. Focal tumors of the liver may be best managed by hepatic lobe resection.

Extra-Hepatic Bile Duct Obstruction
Pathogenesis and Etiology – Extra-hepatic cholangitis, malignancy, pancreatitis, cholelithasis, and liver flukes (Eurytrema procyonis, Platynosomum concinnum) are the major causes of extra-hepatic biliary obstruction in cats. Progressive cholangitis accounts for over 50% of the cases of hepatic duct obstruction, common bile duct obstruction, and progressive hepatobiliary failure.

Clinical Features – Affected cats have marked persistent hyperbilirubinemia, and marked elevations in serum ALT, AST, ALP, GGT, and serum bile acids. Ultrasonographic evidence of obstruction is obvious, and many cats undergo exploratory laparotomy and biliary decompression.

Diagnosis – As with other feline hepatobiliary disorders, diagnosis of extra-hepatic bile duct obstruction requires careful integration of history, physical examination, laboratory data, and imaging findings.

Prognosis and Therapy – The prognosis for cats with extra-hepatic biliary obstruction, regardless of underlying pathogenesis is guarded to poor, and perioperative morbidity and mortality is high. The majority of cats have a prolonged disease course, and long-term complications include recurring bouts of cholangitis, weight loss, and biliary tract obstruction.

Congenital Portosystemic Shunts
Pathogenesis and Etiology – Diversion of portal blood flow to the central circulation depletes the liver of nutrients, hormones, and growth factors. Portosystemic shunts in cats are generally extra-hepatic and most arise from the left gastric vein. Portosystemic shunting results in poor hepatocyte growth and function, and the liver undergoes progressive atrophy.

Clinical Features and Diagnosis – Affected cats appear stunted, fail to grow, and have excessive salivation perhaps as an early manifestation of hepatoencephalopathy. Cats may manifest other behavioral and neurologic abnormalities such as seizures, dementia, visual disturbances, and ataxia. Onset of clinical signs with feeding and delayed recovery from anesthetic events are reported more frequently with canine portosystemic shunts. Affected cats may have only subtle laboratory abnormalities (mild increases in ALT & AST; mild hypoalbuminemia and hypocholesterolemia; low blood urea nitrogen; and microcytosis). Diagnosis is best achieved by coupling a liver function test (bile salts and/or NH3 quantitations) to a liver imaging technique, e.g., ultrasonography, scintigraphy, or contrast portal venography. Liver biopsy typically reveals portal venous hypoplasia, arterial smooth muscle hypertrophy, hepatocellular atrophy with lipogranulomas, and sometimes periportal sinusoidal dilatation.

Prognosis and Therapy – The prognosis is generally good if recognized early in the course of the disease. Cats are best managed with surgical attenuation or ligation of the shunting vessel. Some cats, especially those with incomplete attenuation of the shunt, may still require medical therapy following surgical repair.

References – Available upon request.