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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 cats 18 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 2530% 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 g/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: 444446, 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
MEDICAL INVESTIGATION
TREATMENT
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
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). Positivecontrast 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,
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 2adrenergic 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 1950s. 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.
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; 33:695718.
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
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 postoperative phase, but these drugs potently inhibit gastrointestinal transit. Efforts to reduce the dose of opioids or to antagonize their
effects with peripherally acting opioid -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 postoperative 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 -antagonists - Opioid -antagonists like alvimopan and methylnaltrexone may be useful in antagonizing the effects of morphinelike 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 ,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 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 , ,
and sub-types. Opioid receptors are present in the central and peripheral nervous system, as well as the GI tract. There are many
species and site differences, but 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 -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 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
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 agonist is paramount, the patient could be treated concurrently with an opioid
antagonist, methylnaltrexone or alvimopan, both of which will improve GI transit without inhibiting the central analgesic effect of the
opioid 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-HT 3
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 &
31. Becker G, Blum HE. Novel opioid antagonists for opioid-induced bowel dysfunction and post-operative ileus. Lancet 373: 11981206, 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, 6974, 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 pseudoobstruction 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
Autonomic nervous system
Enteric nervous system
Hormones and neuropeptides
Inflammation
Anesthesia
Narcotics
Factors Involved
Sympathetic inhibitory pathways
Substance P, nitric oxide
Vasoactive intestinal peptide; corticotrophin-releasing
factor ligands; calcitonin gene-related peptide ligands
Macrophage and neutrophil infiltration; cytokines and other
inflammatory mediators
General anesthetics
Opiates
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-HT 2a) 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 1990s.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 (I Kr).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., H 2 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 2-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 cisaprides efficacy in the treatment of human constipation and constipationpredominant 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 1adrenoceptors. 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 (GMCs) 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-HT 4 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 opioidinduced 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-HT 4 receptor activation can cause
relaxation or contraction depending on the region, cell type, and animal species. In the dog, the effects of selective 5-HT 4 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 1950s. 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.
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.
References:
1. Hall JA, Washabau RJ. Gastrointestinal prokinetic therapy: dopaminergic antagonist drugs. Compend Contin Educ Pract Vet 19(2):
214-221, 1997.
2. Biancani P, Barwick K, Selling J, et al: Effects of acute experimental esophagitis in mechanical properties of lower esophageal
sphincter function. Gastroenterology 87:8-16, 1984.
3. Eastwood G, Castell DO, Higgs RH: Experimental esophagitis in cats impairs lower esophageal sphincter function in the cat.
Gastroenterology 69:146-153, 1975.
4. Hall JA, Solie TN, Seim HB, et al. Effect of metoclopramide on fed-state gastric myoelectric and motor activity in dogs. Am J Vet
Res 57: 1616-1622, 1996.
5. Orihata M, Sarna SK. Contractile mechanisms of action of gastroprokinetic agents: cisapride, metoclopramide, and domperidone.
Amer J Physiol 266: G665-G676, 1994.
6. Summers RW, Yanda R, Prihoda M, et al.: A comparative study of the effects of four motor-stimulating agents on canine jejunal
spike bursts. Scand J Gastroenterol 23: 1173-1181, 1988.
7. Washabau RJ and Elie M. Anti-Emetic Therapies. In, Kirk R and Bonagura J, eds. Current Veterinary Therapy XII. 12th ed.
Philadelphia: WB Saunders Co., 1995, 679-684.
8. Janssen P, Prins NH, Meulemans AL, et al. Pharmacological characterization of the 5-HT receptors mediating contraction and
relaxation of canine isolated proximal stomach smooth muscle. Brit J Pharm 136: 321-329, 2002.
9. Washabau RJ, Hall JA. Clinical pharmacology of cisapride. JAVMA 207: 1285-1288, 1995.
10. Washabau RJ, Hall JA. Gastrointestinal prokinetic therapy: serotonergic drugs. Compend Contin Educ Pract Vet 19(4): 473-480,
1997.
11. Drici MD, Ebert SN, Wang WX, et al. Comparison of tegaserod and its main metabolite with cisapride and erythromycin on cardiac
repolarization in the isolated rabbit heart. J Cardiovasc Pharmacol 34: 82-88, 1999.
12. Clark S et al.: Comparison of potential cytoprotective action of sucralfate and cimetidine - studies with experimental feline
esophagitis. Amer J Med 83: 56, 1987.
13. Washabau RJ. Diseases of the esophagus. In, Ettinger SJ and Feldman EC, eds. Textbook of Veterinary Internal Medicine. 5th ed.
Philadelphia: WB Saunders Co., 2000, pp. 1142-1153.
14. Washabau RJ, Holt DE. Pathophysiology of Gastrointestinal Disease. In, Slatter D, ed. Textbook of Veterinary Surgery. 3rd
edition. Philadelphia: WB Saunders Co., 2003, pp 530-552.
15. Cohen ML, Susemichel AD, Bloomquist W, et al.: 5-HT4 receptors in rat but not rabbit, guinea pig, or dog esophageal muscle. Gen
Pharmacol 25: 1143-1148, 1994.
16. Edelbroek M, Schuurkes JAJ, de Ridder WJE, et al.: Effect of cisapride on myoelectrical and motor responses of
antropyloroduodenal lipid and antral tachygastria in conscious dogs. Dig Dis Sci 40: 901-911, 1995.
17. Schemann M, Ehrlein HJ: 5-hydroxytryptophan and cisapride stimulate propulsive jejunal motility and transit of chyme in dogs.
Digestion 34: 229-235, 1986.
18. Hasler AH, Washabau RJ. Cisapride stimulates contraction in feline idiopathic megacolonic smooth muscle. J Vet Intern Med
11(6): 313-318, 1997.
19. Washabau RJ and Sammarco J. Effect of cisapride on colonic smooth muscle function. Am J Vet Res 57: 541-546, 1996.
20. Aboumarzouk OM, Agarwal T, Antakia R, et al. Cisapride for intestinal constipation (review). The Cochrane Collaboration, 2011;
http://www.thecochranelibrary.com
21. Curran MP, Robinsoni DM. Mosapride - Use in gastrointestinal disorders. Drugs 68(7):981-991, 2008.
22. Mine T, Yoshikawa Y, Oku S, et al. Comparison of effect of mosapride citrate and existing 5-HT4 receptor agonists on
gastrointestinal motility, in vivo and in vitro. J. Pharm. Exp. Ther. 283: 1000-1008, 1997.
23. Tsukamoto A, Ohno K, Tsukagoshi T, et al. Ultrasonographic evaluation of vincristine-induced gastric hypomotility and the
prokinetic effect of mosapride citrate in dogs. J. Vet. Intern. Med. 24(3): 721, 2010.
24. Briejer MR, Van Daele P, Bosmans J-P, et al. Dose-dependent effects after oral and intravenous administration of R093877 on
colonic motility in conscious dogs. Gastroenterology 112: A704, 1997a.
25. Briejer MR, Ghoos E, Eelen J, et al. Serotonin 5-HT 4 receptors mediate the R093877-induced changes in contractile patterns in
the canine colon. Gastroenterology 112: A705, 1997d.
26. Prins NH, Van Haselen JF, Lefebvre RA, et al. Pharmacological characterization of 5-HT receptors mediating relaxation of canine
isolated rectum circular smooth muscle. Brit J Pharmacol 127(6): 1431-1437, 1999.
27. Briejer MR, Engelen M, Jacobs J, et al. R093877 enhances defecation frequency in conscious cats. Gastroenterology 112: A705,
1997c.
28. Briejer MR, Meulemans AL, Wellens A, et al. R09387 dose dependently accelerates delayed gastric emptying in conscious dogs.
Table 52-1. Mechanisms, sites of activity, indications, and doses of currently available gastrointestinal prokinetic agents.
Drug Classification/Mechanism
Sites of Activity
Indications
Other Properties
2-adrenergic antagonist
2-adrenergic antagonist
5-HT4-serotonergic
ileus/pseudo-obstruction
antagonist
Domperidone
gastroesophageal reflux,
delayed gastric emptying,
Dose
GES, CRTZ
Vomiting disorders,
gastroesophageal reflux
5-HT3-serotonergic
0.05-0.10 mg/kg PO BID
2-adrenergic antagonist
2-adrenergic antagonist
5-HT3-serotonergic
(doses as high as
5-HT1-serotonergic
5-HT2-serotonergic
Mosapride
Stomach
None
Prucalopride
Stomach, colon
None
Intestine, colon
Constipation,
5-HT1-serotonergic
5-HT3-serotonergic
Tegaserod
antagonist
Motilin-like Drugs
Erythromycin
antagonist
ileus/pseudo-obstruction
GES, stomach,
Gastroesophageal reflux,
intestine, colon
Stomach, colon
H2 histaminergic
H2 histaminergic
constipation
Esophagus
Stomach
Diabetic gastroparesis
Colon
Constipation
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 antigenpresenting 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-, TNF-, 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-, 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 downregulates 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 , , and isoenzyme expression is downregulated, PKC and isoenzyme expression is up-regulated, and the cytosol-to-membrane translocation of PKC is impaired. The Ltype 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. Crohns 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 Crohns 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 , , 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.
Pathogenetic
Histologic
Pathophysiologic
Clinical
Imaging
I.B.D
.
Immunologic
Genetic
Enteric
Neuron
SP
ACh
M2
Smooth Muscle
Cell
C
PK
2+
M3
Ca o
Ko
PLA 2
Ca2+
PKC
IK B
NFKB
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 (Creactive 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)
,-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-HT 3 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
2-Adrenergic Antagonists - These drugs must be used carefully as they can activate 2-adrenergic receptors in the chemoreceptor trigger zone and
cause vomiting.
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 steroidsparing 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. Evidencebased 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.
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, transabdominal 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-HT 2 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, its 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 dont 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, -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