G.I. and Liver Disease
Robert J. Washabau, VMD, PhD, DCAVIM
Professor of Medicine and Department Chair
University of Minnesota
The Eight Principles of Therapy of Canine Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) may be defined using clinical, pathogenetic, imaging, histologic, immunologic, pathophysiologic, and genetic criteria.
IBD has been defined clinically as a spectrum of gastrointestinal disorders associated with chronic inflammation of the stomach, intestine and/or colon of unknown etiology. A clinical diagnosis of IBD is considered only if affected animals have: (1) persistent (>3 weeks in duration) gastrointestinal signs (anorexia, vomiting, weight loss, diarrhea, hematochezia, mucousy feces), (2) failure to respond to symptomatic therapies (parasiticides, antibiotics, gastrointestinal protectants) alone, (3) failure to document other causes of gastroenterocolitis by thorough diagnostic evaluation, and (4) histologic diagnosis of benign intestinal inflammation. Small bowel and large bowel forms of IBD have been reported in both dogs and cats, although large bowel IBD appears to be more prevalent in the dog.
IBD has been defined histologically by the type of inflammatory infiltrate (neutrophilic, eosinophilic, lymphocytic, plasmacytic, granulomatous), associated mucosal pathology (villus atrophy, fusion, crypt collapse), distribution of the lesion (focal or generalized, superficial or deep), severity (mild, moderate, severe), mucosal thickness (mild, moderate, severe), and topography (gastric fundus, gastric antrum, duodenum, jejunum, ileum, cecum, ascending colon, descending colon). As with small intestinal IBD, subjective interpretation of large intestinal IBD lesions has made it difficult to compare tissue findings between pathologists. Subjectivity in histologic assessments has led to the development of several IBD grading systems.
IBD has been defined immunologically by the innate and adaptive response of the mucosa to gastrointestinal antigens. Although the precise immunologic events of canine and feline IBD remain to be determined, a prevailing hypothesis for the development of IBD is the loss of immunologic tolerance to the normal bacterial flora or food antigens, leading to abnormal T cell immune reactivity in the gut microenvironment. Genetically engineered animal models (e.g., IL-2, IL-10, and T cell receptor knockouts) that develop IBD involve alterations in T cell development and/or function suggesting that T cell populations are responsible for the homeostatic regulation of mucosal immune responses. Immunohistochemical studies of canine IBD have demonstrated an increase in the T cell population of the lamina propria, including CD3+ cells and CD4+ cells, as well as macrophages, neutrophils, and IgA-containing plasma cells. Many of the immunologic features of canine IBD can be explained as an indirect consequence of mucosal T cell activation. Enterocytes are also likely involved in the immunopathogenesis of IBD. Enterocytes are capable of behaving as antigen-presenting cells, and interleukins (e.g., IL-7 and IL-15) produced by enterocytes during acute inflammation activate mucosal lymphocytes. Up-regulation of Toll-like receptor 4 (TLR4) and Toll-like receptor 2 (TLR2) expression contribute to the innate immune response of the colon. Thus, the pathogenesis and pathophysiology of IBD appears to involve the activation of a subset of CD4+ T cells within the intestinal epithelium that overproduce inflammatory cytokines with concomitant loss of a subset of CD4+ T cells, and their associated cytokines, which normally regulate the inflammatory response and protect the gut from injury. Enterocytes, behaving as antigen-presenting cells, contribute to the pathogenesis of this disease.
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.
IBD may be defined by genetic criteria in several animal species. Crohn's disease and ulcerative colitis are more common in certain human genotypes, and a mutation in the NOD2 gene (nucleotide-binding oligomerization domain2) has been found in a sub-group of patients with Crohn's disease. Genetic influences have not yet been identified in canine or feline IBD, but certain breeds (e.g., German shepherds, Boxers) appear to be at increased risk for the disease.
The pathophysiology of large intestinal IBD is explained by at least two interdependent mechanisms: the mucosal immune response, and accompanying changes in motility.
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- . Other studies of canine colonic IBD have demonstrated increased numbers of mucosal IgA- and IgG-containing cells, nitrate, CD3+ T cells, nitric oxide (NO), and inducible nitric oxide synthase (iNOS) in the inflamed colonic mucosa. Increases in the CD3+ positive T cell population of the inflamed colon are consistent with changes reported in the inflamed canine intestine. Thus, there are important similarities and differences between small and large bowel IBD.
Experimental studies of canine large intestinal IBD have shown that many of the clinical signs (diarrhea, passage of mucus and blood, abdominal pain, tenesmus, and urgency of defecation) are related to motor abnormalities of the colon. Ethanol and acetic acid perfusion of the canine colon induces a large bowel form of IBD syndrome indistinguishable from the natural condition. Inflammation in this model suppresses the normal phasic contractions of the colon, including the migrating motility complex, and triggers the emergence of giant migrating contractions (GMCs). The appearance of these GMCs in association with inflammation is a major factor in producing diarrhea, abdominal cramping, and urgency of defecation. GMCs are powerful lumen-occluding contractions that rapidly propel pancreatic, biliary, and intestinal secretions in the fasting state, and undigested food in the fed state, to the colon to increase its osmotic load. Malabsorption results from direct injury to the epithelial cells and from ultrarapid propulsion of intestinal contents by giant migrating contractions (GMCs) so that sufficient mucosal contact time is not allowed for digestion and absorption to take place.
Inflammation impairs the regulation of the colonic motility patterns at several levels, i.e., enteric neurons, interstitial cells of Cajal, and circular smooth muscle cells. Inflammation-induced changes in the amplitude and duration of the smooth muscle slow wave plateau potentials contribute to the suppression of rhythmic phasic contractions (RPCs). These alterations likely have their origin in structural as well as functional damage to the interstitial cells of Cajal.. At the same time that inflammation suppresses the (RPCs), inflammation sensitizes the colon to the stimulation of GMCs by the neurotransmitter substance P. These findings suggest that SP increases the frequency of GMCs during inflammation, and that selective inhibition of GMCs during inflammation may minimize the symptoms of diarrhea, abdominal discomfort, and urgency of defecation associated with these contractions.
Inflammation suppresses the generation of tone and phasic contractions in the circular smooth muscle cells through multiple molecular mechanisms. Inflammation shifts muscarinic receptor expression in circular smooth muscles from the M3 to the M2 subtype. This shift has the effect of reducing the overall contractility of the smooth muscle cell. Inflammation also impairs calcium influx and down-regulates the expression of the L-type calcium channel, which may be important in suppressing phasic contractions and tone while concurrently stimulating GMCs in the inflamed colon. Changes in the open-state probability of the large conductance calcium-activated potassium channels (KCa) partially attenuate this effect. Inflammation also modifies the signal transduction pathways of circular smooth muscle cells. Phospholipase A2 and protein kinase C (PKC) expression and activation are significantly altered by colonic inflammation and this may partially account for the suppression of tone and phasic contractions. PKC , ?, and isoenzyme expression is down-regulated, PKC and isoenzyme expression is up-regulated, and the cytosol-to-membrane translocation of PKC is impaired. The L-type calcium channel, already reduced in its expression, is one of the molecular targets of PKC. Inflammation also activates the transcription factor NF- B which further suppresses cell contractility.
Schematic: 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.
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.
Complete blood counts, serum chemistries, and urinalyses are often normal in mild cases of large bowel IBD. Chronic cases may have one or more subtle abnormalities. One review of canine and feline IBD reported several hematologic abnormalities including mild anemia, leukocytosis, neutrophilia with and without a left shift, eosinophilia, eosinopenia, lymphocytopenia, monocytosis, and basophilia. The same study reported several biochemical abnormalities including increased activities of serum alanine aminotransferase and alkaline phosphatase, hypoalbuminemia, hypoproteinemia, hyperamylasemia, hyperglobulinemia, hypokalemia, hypocholesterolemia, and hyperglycemia. No consistent abnormality in the complete blood count or serum chemistry has been identified.
A scoring index for disease activity in canine IBD was recently developed that relates severity of clinical signs to serum acute-phase protein (C-reactive protein, serum amyloid A) concentrations. The canine IBD activity index (CIBDAI) assigns levels of severity to each of several gastroenterologic signs (e.g., anorexia, vomiting, weight loss, diarrhea), and it appears to be a reliable index of mucosal inflammation in canine IBD. Interestingly, both the activity index and serum concentrations of C-reactive protein (CRP) improve with successful treatment, suggesting that serum CRP is suitable for the laboratory evaluation of therapy in canine IBD. Other acute-phase proteins were less specific than CRP. One important caveat that should be emphasized is that altered CRP is not prima facie evidence of gastrointestinal inflammation. Concurrent infections or other inflammatory conditions could cause an acute-phase response, including CRP, in affected patients.
Treatment: Management of IBD consists of 1) dietary therapy, 2) exercise, 3) antibiotics, 4) probiotics, 5) anti-diarrheal agents, 6) restoration of normal motility, 7) anti-inflammatory or immunosuppressive therapy, and 8) behavioral modification.
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 - 294 references. Available upon request.
A more detailed review of diseases of the large intestine may be found in: Washabau RJ. Diseases of the Large Intestine. In, Textbook of Veterinary Internal Medicine, 6th edition, Ettinger SJ and Feldman EC, editors. WB Saunders Co, Philadelphia, PA, 2005: 1378-1408.
Guilford WG. The gastrointestinal tract and adverse reactions to food. In Consultations in Feline Internal Medicine, ed August JR. WB Saunders, Philadelphia, pp 113-117, 2000.
Jergens AE, Schreiner CA, Frank DE, et al. A scoring index for disease activity in canine inflammatory bowel disease. J Vet Intern Med 17: 291, 2003.
Ridyard AE, Nuttall TJ, Else RW, et al. Evaluation of Th1, Th2 and immunosuppressive cytokine mRNA expression within the colonic mucosa of dogs with idiopathic lymphocytic-plasmacytic colitis. Vet Immunol Immunopathol 86: 205, 2002.
Washabau RJ, Holt DE. Pathophysiology of gastrointestinal disease. In, Textbook of Veterinary Surgery, Slatter D, ed. 3rd edition. WB Saunders, Philadelphia, 530-552, 2003.
New Developments in the Therapy of Difficult Vomiting Disorders
I. History Taking
A complete and detailed history is the first step in establishing a correct diagnosis of a vomiting disorder. The patient's signalment will usually establish some level of probability for many of the differential diagnoses. For example, adrenocortical insufficiency would be an important differential diagnosis for a two year old dog presented with an acute history of vomiting and muscular weakness, with or without diarrhea. Similarly, the acute onset of vomiting in an unvaccinated puppy should alert the veterinarian to the possibility of an infectious disease, for example, parvoviral or distemper viral gastroenteritis. Chronic vomiting in an eleven year old dog, on the other hand, would elicit a different set of differential diagnoses.
Following consideration of the patient's signalment, the history taking should ascertain vaccination status, travel history, and any recent dietary changes. Previous medical problems, medication history, and the possible ingestion of toxic substances or foreign bodies should also be ascertained. These pieces of information can be quite useful in formulating a list of differential diagnoses. Next, the veterinarian should be convinced that the pet owner is describing vomiting, and not some other sign. For example, the coughing associated with inflammatory disorders of the upper airway will often be described as vomiting by many pet owners. Gagging is also occasionally confused with vomiting. A careful history taking will usually discriminate coughing and gagging from vomiting. Pet owners will also often confuse regurgitation and dysphagia with vomiting. Regurgitation is the passive evacuation of ingested food from the pharynx and/or esophagus; the premonitory signs of retching and abdominal contractions seen with vomiting are not observed with regurgitation. The description of regurgitation by a pet owner would suggest a more proximal disorder of the pharynx or esophagus. Dysphagia or difficulty in swallowing would also suggest a more proximal disorder of the pharynx.
The history taking should then elicit the duration, frequency, and time of vomiting episodes, as well as the relationship of vomiting to food and water consumption. Disorders of vomiting that are of short duration are usually self-limiting and not worthy of extensive investigation; chronic vomiting histories, on the other hand, are more serious and certainly require a more detailed investigation. Frequent vomiting usually occurs as result of systemic, metabolic, or endocrine disorders or severe inflammatory disorders of the primary gastrointestinal tract. Vomiting that occurs in the immediate post-prandial period is usually suggestive of overeating, excitement, or disorders of the esophageal body or esophageal hiatus (e.g. hiatal hernia). Conversely, vomiting of undigested or partially digested food 8 or more hours post-prandially would suggest a distal gastric (corpus, antrum, and pylorus) motility disorder or obstruction. Vomiting of water would be more suggestive of a proximal gastric (cardia, fundus) motility disorder. Vomiting during the early morning hours often may result from gastroesophageal reflux.
Finally, the physical characteristics of the vomitus, including the color, amount, odor, consistency, and the presence or absence of blood or bile should be ascertained. Undigested food in the vomitus implies a gastric etiology, while digested food (chyme) implies an intestinal etiology for the vomiting. The presence of blood in the vomitus implies disruption of the gastrointestinal mucosa; blood may appear as frank red clots or as a dark brown "coffee-grounds" material resulting from acid proteolysis. Bile in the vomitus usually suggests only that the pylorus has permitted bile reflux. However, bile salts are known to increase the permeability of the gastric mucosal barrier resulting in a syndrome of bile reflux gastritis. Bilious vomiting, therefore, might provide a clue to the pathogenesis of the disorder. A fecal odor has been described with lower intestinal (jejuno-ileal) obstruction.
II. Physical Examination
Examination of the mouth and pharyngeal structures often provide important clues to the pathogenesis of vomiting, e.g. uremic breath or ulcers, icteric mucous membranes, severe pharyngitis or pharyngeal string foreign bodies. The physical examination finding of generalized lymphadenopathy would suggest neoplasia or a systemic inflammatory disease as the pathogenesis of the vomiting. Hence, all lymph nodes should be carefully palpated to determine if they are enlarged and/or painful. The presence of fever on physical examination would likewise suggest an inflammatory pathogenesis for the vomiting disorder. Extreme bradycardia or other rhythm disturbance detected upon cardiac auscultation might be an important sign of a metabolic disturbance such as adrenocortical insufficiency or septic shock. The abdomen should then be carefully palpated for effusion (e.g. peritonitis), masses (e.g. carcinomatosis or other malignancy), pain (e.g. peritonitis, pancreatitis, or nephritis), gaseous or fluid distension of the intestine (e.g. obstruction), kidney size and shape (e.g. end-stage fibrotic kidneys or nephritis), liver size (e.g. hepatitis), uterine distension (e.g. pyometra), and urinary bladder size (e.g. bladder obstruction). Rectal examination might also provide some evidence of pain or hematochezia (e.g. colitis), worms (e.g. hook or whipworms), or painful prostatomegaly (e.g. prostatitis or prostatic neoplasia). Finally, examination of the central nervous system should be considered, especially in the animal in which the cause of vomiting is not so obvious. Some animals with intervertebral disc disease will vomit because of pain.
III. Differential Diagnosis
After identifying problems from the history and physical examination, a reasonable list of differential diagnoses may then be considered based upon pathogenetic mechanism: abdominal alimentary, abdominal extra-alimentary, systemic-metabolic-endocrine, drug-induced, toxicity, diet-related, and neurologic disorders.
IV. Diagnostic Workup
If a definitive diagnosis is not established from the history and physical examination, then the following "initial tests" are warranted: complete blood count, serum chemistry, urinalysis, fecal parasitologic examination, and abdominal radiographs.
Peripheral eosinophilia in a complete blood count would suggest the possibilities of systemic mast cell disease, intestinal parasitism, or adrenocortical insufficiency. Leukopenia and neutropenia might be observed in the acute phase of a viral gastroenteritis. Leukocytosis, on the other hand, might suggest an inflammatory disorder like acute pancreatitis. The serum chemistry will often help identify systemic, metabolic, and endocrine causes of vomiting. For example: 1) azotemia and hyperphosphatemia suggest that the vomiting has resulted from chronic renal failure; 2) hyperglycemia, acidosis, glucosuria, and ketonuria suggest diabetic ketoacidosis as the cause of vomiting; 3) hyponatremia and hyperkalemia suggest adrenocortical insufficiency; 4) amylasemia and lipasemia suggest acute pancreatitis; 5) increases in serum liver enzyme activities (ALT, AST, ALP) suggest primary liver disease; and, 6) hypercalcemia suggests parathyroid or other malignancy. Urinalysis will be useful in differentiating pre-renal and primary renal azotemia, while fecal examination may provide evidence of intestinal helminth infestation.
Survey radiographs of the abdomen are certainly indicated in the initial workup of a vomiting disorder. The abdominal radiographs will provide useful information about the abdominal alimentary and extra-alimentary structures. The decision to perform additional tests is based on response to empirical therapies and initial test results. Further tests might include: thoracic radiography, abdominal ultrasonography, contrast radiography, ACTH stimulation, liver function tests, gastrointestinal endoscopy, and laparotomy.
***Adapted from an algorithm kindly provided by Dr. Colin F. Burrows, University of Florida.
V. Anti-Emetic Therapy
Physiology of Emesis: The essential components of the emetic reflex are visceral receptors, vagal and sympathetic afferent neurons, a chemoreceptor trigger zone (CRTZ) located within the area postrema that is sensitive to blood-borne substances, and an emetic center within the reticular formation of the medulla oblongata receiving input from vagal and sympathetic neurons, CRTZ, vestibular apparatus, and cerebral cortex. An important concept dating from the early 1950's is that vomiting occurs either through activation of the CRTZ by blood-borne substances (humoral pathway), or through activation of the emetic center by vago-sympathetic, CRTZ, vestibular, or cerebrocortical neurons (neural pathway). Thus, activation of the CRTZ by a variety of humoral emetogenic substances (e.g. uremic toxins, cardiac glycosides, and apomorphine) is abolished by surgical ablation of the area postrema, but not by vagotomy or sympathectomy. In contrast, neural activation of the emetic center by gastric disease (e.g. gastritis) is abolished by vagotomy or sympathectomy, but not by ablation of the area postrema. Many experimental data have been readily explained by this two-component model. Despite contemporary reexamination, there is still good agreement on the two general patterns of emesis, one humoral and one neural. Current therapy is largely based on these assumptions.
Many of the spontaneous vomiting disorders of cats and dogs, particularly those of the primary gastrointestinal tract, are believed to result from activation of the neural pathway. Vomiting associated with primary gastrointestinal tract disease (e.g., inflammation, infection, malignancy, toxicity) results from activation of visceral receptors, afferent neurons, and the emetic center. Efferent information transmitted back to the gastrointestinal tract stimulates the motor correlates of vomiting (retrograde duodenal and gastric contractions, relaxation of the caudal esophageal sphincter, gastroesophageal reflux, opening of the proximal esophageal sphincter, and evacuation of gastrointestinal contents). A neural pathway can also be involved in vomiting associated with motion sickness. Motion within the semicircular canals is transduced to vestibulo-cochlear neurons that ultimately synapse in the CRTZ or emetic center. Cats and dogs experience motion sickness, although the neuroanatomy and pharmacology appear to be somewhat different between the two species. Histaminergic neurons and the CRTZ are involved in motion sickness in the dog, whereas neither are involved in motion sickness in the cat. A neural pathway involving cerebrocortical neurons may be involved in vomiting disorders associated with anxiety or anticipation, but these are probably more important in human beings.
The essential component of the humoral pathway is the chemoreceptor trigger zone (CRTZ) located within the area postrema that is sensitive to blood-borne substances. Receptors within the CRTZ may be activated by many endogenous (e.g., uremic-, hepatoencephalopoathic-, or endo-toxins) and exogenous (e.g., digitalis glycosides, apomorphine) blood-borne substances. Most pharmacological approaches to anti-emetic therapy have been based on neurotransmitter-receptor interactions at the CRTZ, emphasizing the humoral pathway of emesis. The neural pathway has received much less emphasis even though it is a much more important pathway.
Pharmacology of Emesis: Vomiting is initiated through activation of one or more neurons in the CRTZ or emetic center.
Chemoreceptor Trigger Zone. Neurochemical studies have demonstrated the presence of several neurotransmitters: dopamine, norepinephrine, 5-hydroxytryptamine (5-HT, serotonin), acetylcholine, histamine, and enkephalins; their respective receptors or binding sites: D2 dopaminergic, ?2 adrenergic, 5-HT3 serotonergic, M1 cholinergic, H1 and H2 histaminergic, and ENK? and ENK? enkephalinergic; and their respective synthetic or degradative enyzmes: DOPA decarboxylase, dopamine ? hydroxylase, 5-hydroxytryptophan decarboxylase, choline acetyltransferase, histidine decarboxylase, and enkephalinase. Some neurotransmitter-receptor systems are probably more important than others. For example, apomorphine, a D2 dopamine receptor agonist, is a potent emetic agent in the dog, but it does not readily induce emesis in the cat. This finding has two important implications: 1) CRTZ D2 dopamine receptors are not as important in mediating humoral emesis in the cat, and 2) D2 dopamine receptor antagonists (e.g. metoclopramide) are not as useful as anti-emetic agents in the cat. Xylazine, an ?2 adrenergic agonist, is a more potent emetic agent in the cat than in the dog. Xylazine's effect suggests that ?2 adrenergic antagonists may be more useful anti-emetic agents than D2 dopamine antagonists in the cat. Cancer chemotherapy (e.g. cisplatinum, doxorubicin, cyclophosphamide) induced-emesis is mediated by activation of 5-HT3 receptors in the CRTZ of the cat, while visceral and vagal afferent 5-HT3 receptors may be more importantly involved in the dog. Antagonists of the 5-HT3 receptor are efficacious in the prevention of emesis associated with cisplatinum and other chemotherapy in cats and dogs. Finally, while histamine, and H1 and H2 histaminergic receptors, have been demonstrated in the CRTZ of the dog, they have not yet been demonstrated in the cat. Histamine is a potent emetic agent in the dog, but the cat seems resistant to its emetic effects. H1 histaminergic antagonists (e.g., diphenhydramine) are ineffective anti-emetic agents for motion sickness in the cat.
Emetic Center. At the present time, the 5-HT1A and ?2 adrenergic receptors are the only documented receptors involved in the regulation of emesis at the level of the emetic center. It has recently been shown that agonists of the 5-HT1A receptor (e.g. flesinoxan, 8-OH-DPAT, buspirone) suppress emesis associated with motion sickness in cats. These drugs have not been approved for use in the cat, however. The ?2 adrenergic receptor, on the other hand, may be antagonized with currently available anti-emetic drugs. The emetic center ?2 receptor, as well as the CRTZ ?2 receptor, may be antagonized by a pure ?2 antagonist, e.g. yohimbine, or by mixed ?1/?2 antagonists, e.g. prochlorperazine and chlorpromazine. It is likely, however, that most of the anti-emetic effect of the ? receptor antagonists results from antagonism of the CRTZ ?2 adrenergic receptor.
Vestibular Apparatus. Muscarinic M1 receptors and acetylcholine have been demonstrated in the vestibular apparatus of the cat. Mixed M1/M2 antagonists, e.g. atropine, and pure M1 antagonists, e.g. pirenzepine, inhibit motion sickness in the cat. It is not clear, however, whether the anti-emetic effect of these drugs is due solely to M1 receptor antagonism at the vestibular apparatus. Other sites (e.g. cerebral cortex, reticular formation, area postrema) of antagonism are possible.
Cerebral Cortex. Opioids (e.g. cannabinoids and nabilone) and benzodiazepines (e.g. diazepam, lorazepam) have been used to reduce anticipatory nausea and vomiting in human beings undergoing cytotoxic drug therapy. Cerebrocortical opioid and benzodiazepine receptors have been implicated but have not been very well characterized pharmacologically. These receptors will likely be of minor significance in the pathogenesis of most vomiting disorders in the cat.
Gut Afferents. There are a number of different mechanisms by which stimuli arising from the gastrointestinal tract cause emesis. For example, ingested toxins, cell degeneration or necrosis, inflammation, luminal distension, chemotherapy, and radiation therapy all induce emesis. Of the many receptors found in the gastrointestinal tract, 5-HT3 receptors likely play an important role in the initiation of emesis. It is now well established that cytotoxic drugs cause 5-HT release from enterochromaffin cells in the gastrointestinal tract which then activates 5-HT3 receptors in afferent vagal fibers (dog) or CRTZ (cat). Vomiting induced by 5-HT release and 5-HT3 receptor activation is abolished by pre-treatment with 5-HT3 antagonists, e.g. ondansetron, granisetron, and tropisetron. Metoclopramide is a weak antagonist of 5-HT3 receptors but does not seem to be very effective in preventing chemotherapy-induced emesis.
Gut Efferents. Vagal efferent and myenteric neurons initiate the complex excitation and inhibition of visceral smooth muscle (e.g., retrograde duodenal and gastric contractions, relaxation of the caudal esophageal sphincter, gastroesophageal reflux, opening of the proximal esophageal sphincter, and evacuation of gastrointestinal contents) that culminates in emesis. A number of receptors have been identified on myenteric neurons and gastrointestinal smooth muscle cells that regulate gastric emptying and/or intestinal transit. These include 5-HT4 serotonergic (neuronal), D2 dopaminergic (neuronal), M2 cholinergic (smooth muscle), and motilin (smooth muscle - dog only) receptors. Cisapride, a substituted benzamide, facilitates gastric emptying by activating pre-synaptic neuronal 5-HT4 receptors. Metoclopramide is a weak gastric prokinetic agent in the cat, and is believed to facilitate gastric emptying via agonism of 5-HT4 serotonergic receptors, or via antagonism at D2 dopamine receptors. Canine gastric emptying is also regulated by motilin, a hormone that is released episodically from gastrointestinal endocrine cells. Motilin initiates phase III of the migrating myoelectric complex and facilitates gastric emptying during the fasting state. Low doses of erythromycin (0.5-1.0 mg/kg q 8 h PO, IV) have been shown to stimulate motilin release and facilitate gastric emptying in the dog. The role of motilin in the regulation of feline gastric emptying is incompletely understood. Motilin-like macrolide antibiotics increase tone in the feline caudal esophageal sphincter, but their role in regulation of motility is incompletely understood.
A number of anti-emetic drugs have been formulated based on the aforementioned neurotransmitter-receptor systems. These drugs may be classified as: ?2 adrenergic antagonists, D2 dopaminergic antagonists, H1 and H2 histaminergic antagonists, M1 muscarinic cholinergic antagonists, ENK enkephalinergic mixed agonists/antagonists, and 5-HT3 serotonergic antagonists. The 5-HT4 serotonergic agonists are not direct anti-emetic drugs per se, but may have an indirect anti-emetic effect by promoting gastrointestinal motility.
Rational Use of Anti-Emetic Agents in the Diagnosed Patient:
The Spectrum of Feline Exocrine Pancreatic Disease:
More Complicated Than We Thought
Acute necrotizing pancreatitis is but one of many pathologies involving the feline exocrine pancreas. Based on a series of reports over the past decade,1-11 we now have a much better understanding of the natural history of these diseases. A pathologic classification of feline exocrine pancreatic disease has been used to delineate these disorders although it should be emphasized that significant overlap exists between several disease categories, particularly with regard to acute and chronic forms of pancreatitis.
" Acute necrotizing pancreatitis (ANP) - This lesion is characterized by pancreatic acinar cell and peri-pancreatic fat necrosis (>50% of the pathology), with varying amounts of inflammation, hemorrhage, mineralization, and fibrosis. Inflammation may be present, but necrosis is the predominant feature. Reports of this condition were uncommon prior to the early 1990's, probably related to difficulties in diagnosis as well as lower incidence of disease. ANP is now a well-recognized gastrointestinal disorder of significant morbidity and mortality in the domestic cat.1-10
Acute suppurative pancreatitis (ASP) - Acute suppurative pancreatitis differs from acute necrotizing pancreatitis in that neutrophilic inflammation accounts for >50% of the pancreatic pathology. Necrosis may be present, but neutrophilic inflammation is the predominant feature. ASP is less common than ANP, appears to affect younger animals, and may have a differing pathogenesis.2,5,6,10
Chronic non-suppurative pancreatitis (CP) - This lesion is characterized by lymphocytic inflammation, fibrosis, and acinar atrophy. Necrosis and suppuration may be present in small amounts, but lymphocyte infiltration is the predominant feature. Ante-mortem differentiation of CP and APN cannot be made on the basis of clinical, clinicopathologic, or imaging findings;10 histopathology remains the only dependable method of differentiating these two disorders.10 Chronic non-suppurative pancreatitis and acute necrotizing pancreatitis may vary in their pathogeneses or they may represent a continuum of disease from necrosis to inflammation and fibrosis.1,10
Pancreatic nodular hyperplasia - Nodules of pancreatic acinar or duct tissue are distributed throughout the pancreatic parenchyma. Fibrosis, inflammation, necrosis, and hemorrhage are not features of this condition. The clinical significance of this lesion is unknown. Pancreatic nodular hyperplasia is often detected at the time of routine abdominal ultrasonography or as an incidental finding at necropsy. Its importance appears to reside in the need to differentiate its ultrasonographic characteristics from those of acute necrotizing pancreatitis.
Pancreatic neoplasia - Neoplastic disorders of the pancreas may be primary (e.g., adenoma, adenocarcinoma) or secondary, and they are classified as benign or malignant. Pancreatic adenocarcinoma is the most common malignancy of the feline exocrine pancreas and is of ductal (primarily) or acinar origin. Neoplastic infiltration may be accompanied by necrosis, inflammation, fibrosis, hemorrhage, or mineralization in some instances.
Pancreatic pseudocyst - Pancreatic pseudocyst is a common complication of pancreatitis in humans, and a not-so-common complication in cats and dogs.12 Pancreatic pseuodcyst is a non-epithelial lined cavitary structure containing fluid, pancreatic cells, and/or enzyme. It is observed at the time of ultrasound, CT scan, surgery, or necropsy. Its importance appears to reside in the need to differentiate its ultrasonographic characteristics from those of pancreatic abscessation.
Pancreatic abscess - Pancreatic abscess is a circumscribed collection of purulent material involving the right or left lobe of the pancreas. Like pseudocyst, pancreatic abscessation appears to be a complication of pancreatitis in humans and dogs.13 The incidence and significance of this lesion in the cat are unknown. Medical and surgical therapies have been used to manage pancreatic abscesses in the dog.
Pancreatic atrophy - Atrophy may result from degeneration, involution, necrosis, or apoptosis of the exocrine portion of the gland. Most feline cases are believed to represent the end stage of chronic pancreatitis. The endocrine portion of the gland may or may not be involved in the same process. Exocrine pancreatic insufficiency is the clinical syndrome that results from 95% or greater loss of exocrine pancreatic function. Affected animals develop a classic maldigestion syndrome characterized by weight loss, steatorrhea, and diarrhea.11
The etiologies of acute necrotizing pancreatitis are probably not yet completely recognized. Biliary tract disease, gastrointestinal tract disease, ischemia, pancreatic ductal obstruction, infection, trauma, organophosphate poisoning, and lipodystrophy all have known associations with the development of acute necrotizing pancreatitis in the cat. Hypercalcemia, idiosyncratic drug reactions, and nutritional causes are suggested but poorly documented causes of the disease.
Concurrent Biliary Tract Disease - Concurrent biliary tract pathology has a known association with acute necrotizing pancreatitis in the cat. Cholangitis is the most important type of biliary tract disease for which an association has been made,14 but other forms of biliary tract pathology (e.g., stricture, neoplasia, and calculus) have known associations.2,9 Epidemiologic studies14 have shown that cats affected with suppurative cholangitis have significantly increased risk for pancreatitis. The pathogenesis underlying this association is not entirely clear but relates partly to the anatomic and functional relationship between the major pancreatic duct and common bile duct in this species.15,16 Unlike the dog, the feline pancreaticobiliary sphincter is a common physiological and anatomic channel at the duodenal papilla. Mechanical or functional obstruction to this common duct readily permits bile reflux into the pancreatic ductal system. Bile salt perfusion (e.g., 1-15 mM sodium cholate or glycodeoxycholate) of the major pancreatic duct induces changes in the permeability of the pancreatic duct,17,18 and sustained elevations in ductal pressure (> 40 cm H20) and bacterial infection induce pancreatic acinar necrosis.18 Ductal pressures are readily increased by biliary infection, and ductal compression is a predictable consequence of sustained ductal hypertension and pancreatic interstitial edema.18,19
Concurrent Gastrointestinal Tract Disease - Like concurrent biliary tract disease, inflammatory bowel disease (IBD) is an important risk factor for the development of acute necrotizing pancreatitis in the cat.14,20 Several factors appear to contribute to this association: (1) High incidence of inflammatory bowel disease - IBD is a common disorder in the domestic cat.20-22 In some veterinary hospitals and specialty referral centers, IBD is the most common gastrointestinal disorder in cats. (2) Clinical symptomatology of IBD - Vomiting is the most important clinical sign in cats affected with IBD.20-22 Chronic vomiting raises intra-duodenal pressure and increases the likelihood of pancreaticobiliary reflux. (3) Pancreaticobiliary anatomy - The pancreaticobiliary sphincter is a common physiological and anatomic channel at the duodenal papilla,15,16 thus reflux of duodenal contents would perfuse pancreatic and biliary ductal systems. (4) Intestinal Microflora - Compared to dogs, cats have a much higher concentration of aerobic, anaerobic and total (109 vs. 104 organisms/ml) bacteria in the proximal small intestine.23,24 Bacteria readily proliferate in the feline small intestine because of differences in gastrointestinal motility and immunology.25,26 If chronic vomiting with IBD permits pancreaticobiliary reflux, a duodenal fluid containing a mixed population of bacteria, bile salts, and activated pancreatic enzyme would perfuse the pancreatic and biliary ductal systems.27
Ischemia - Ischemia (e.g., hypotension, cardiac disease) is a cause or consequence of obstructive pancreatitis in the cat. Inflammation and edema reduce the elasticity and distensibility of the pancreas during secretory stimulation. Sustained inflammation increases pancreatic interstitial and ductal pressure which serves to further reduce pancreatic blood flow, organ pH, and tissue viability.28-30 Acidic metabolites accumulate within the pancreas because of impaired blood flow.30-32 Ductal decompression has been shown to restore pancreatic blood flow, tissue pH, and acinar cell function.31,32
Pancreatic Ductal Obstruction - Obstruction of the pancreatic duct (e.g., neoplasia, pancreatic flukes, calculi, and duodenal foreign bodies) is associated with the development of acute necrotizing pancreatitis in some cases.9,33 Pancreatic ductal obstruction has marked effects on pancreatic acinar cell function. During ductal obstruction, ductal pressure exceeds exocytosis pressure and causes pancreatic lysosomal hydrolases to co-localize with digestive enzyme zymogens within the acinar cell.34 Co-localization is the underlying pathogenesis for digestive enzyme activation within the acinar cell because lysosomal enzymes (e.g., cathepsin B) readily activate trypsin.34
Infection - Infectious agents have been implicated in the pathogenesis of feline acute necrotizing pancreatitis although none have been reported as important causes of ANP in any of the recent clinical case series.1-10 The pancreas is readily colonized by Toxoplasma gondii organisms during the acute phase of infection.35 In one survey of T. gondii-infected cats, organisms were found in 84% of the cases, although organ pathology was more severe in other organ systems.35 Feline herpesvirus I and feline infectious peritonitis viruses have been implicated as causative agents in several case reports,36 and feline parvoviral infection has been associated with viral inclusion bodies and pancreatic acinar cell necrosis in young kittens.37 Pancreatic (Eurytrema procyonis) and liver fluke (Amphimerus pseudofelineus, Opisthorchis felineus) infections are known causes of feline acute necrotizing pancreatitis in the southeastern United States and Caribbean Basin.33,38 Recent reports of virulent calici viral infections have been reported in multiple cat households or research facilities. Affected cats manifest high fever, anorexia, labored respirations, oral ulceration, facial and limb edema, icterus, and severe pancreatitis.39-41 Caliciviral infection has not been reported in any of the recent clinical case series of feline acute necrotizing pancreatitis,1-10 but some cases of active infection could have been overlooked. The importance of calicivirus infection in the pathogenesis of feline acute pancreatic necrosis remains to be determined.
Trauma - Automobile and fall ('high rise syndrome") injuries have been associated with the development of acute necrotizing pancreatitis in a small number of cases.42,43 These tend to be isolated cases that do not show up as important causes in clinical case surveys.
Organophosphate Poisoning - Organophosphate poisoning is a known cause of acute necrotizing pancreatitis in humans and dogs,44 and several cases have been reported in the cat.2 In one survey, several cats developed ANP following treatment for ectoparasites, and two cats developed ANP following treatment with fenthion.2 Diminishing organophosphate usage will probably lead to a reduced incidence of this lesion.
Lipodystrophy - Lipodystrophy has been cited as an occasional cause of acute necrotizing pancreatitis in the cat,45 but it has not been reported in any of the large clinical case series.
Hypercalcemia - Acute necrotizing pancreatitis develops in association with the hypercalcemia of primary hyperparathyroidism and humoral hypercalcemia of malignancy in humans, and a weak association with hypercalcemia has been reported in dogs.12 Moderate hypercalcemia was found as a pre-existing laboratory finding in 10% of the cases of fatal canine acute pancreatitis.12 Acute experimental hypercalcemia does indeed cause acute pancreatic necrosis and pancreatitis in cats,46,47 but it is probably not very clinically relevant. Acute hypercalcemia is an uncommon clinical finding in feline practice. Chronic hypercalcemia, a more clinically relevant condition, is not associated with changes in pancreatic morphology or function.48
Idiosyncratic Drug Reactions - Therapy with azathioprine, l-asparaginase, potassium bromide and trimethoprim sulfa drugs have been associated with the development of acute necrotizing pancreatitis in the dog.12,49 Similar associations have not been made in the cat. Glucocorticoid administration has been suggested as a cause of acute pancreatitis in the dog, but a firm association has not been confirmed in either species. Indeed, anti-inflammatory doses of glucocorticoids appear to be beneficial in the management of experimental canine acute pancreatic necrosis.50
Nutrition - High fat feedings51 and obesity49 have been associated with the development of pancreatitis in the dog, but similar associations have not been made in the cat. Most recent surveys have associated underweight body condition with the development of feline ANP.2,6,8,10
The acinar and ductal cells of the exocrine pancreas are interspersed between the islet cells of the endocrine pancreas. Like the endocrine pancreas, the exocrine pancreas is a secretory organ with several physiologic functions. Exocrine pancreatic fluid contains: digestive zymogens which initiate protein, carbohydrate, and lipid digestion; bicarbonate and water which serve to neutralize the duodenum; intrinsic factor which facilitates cobalamin (vitamin B12) absorption in the distal ileum; and, anti-bacterial proteins which regulate the small intestinal bacterial flora. Digestive zymogens are secreted primarily by acinar cells, while bicarbonate, water, intrinsic factor, and anti-bacterial proteins are secreted primarily by ductal cells. The two most common disorders of the exocrine pancreas, acute pancreatic necrosis and exocrine pancreatic insufficiency, are readily understood on the basis of these physiologic functions. With acute pancreatic necrosis, premature activation of digestive zymogen within pancreatic acinar cells leads to acinar cell necrosis (trypsin, chymotrypsin, carboxypeptidase), hemorrhage (elastase digestion of blood vessel elastin fibers), and fat necrosis and saponification (lipase digestion of pancreatic, peripancreatic and mesenteric fat). With exocrine pancreatic insufficiency, affected animals develop severe nutrient maldigestion, acid injury to the duodenal mucosa, cobalamin and fat soluble vitamin malabsorption, and bacterial proliferation in the gut (summarized in reference 52).
Pancreatic acinar cells protect themselves from intra-acinar activation of zymogen and acinar cell necrosis through several mechanisms: (1) Potentially harmful digestive enzymes are synthesized in the form of inactive precursors or zymogens in the rough endoplasmic reticulum. (2) Zymogens are then transported to the Golgi complex where they undergo selective glycosylations. Lysosomal hydrolases that are eventually packaged in lysosomes are separated from zymogens bound for export as they pass through the Golgi complex. Lysosomal hydrolases are first phosphorylated at the 6 position of mannose residues, bound to receptors specific for 6-phosphoryl mannose, and then transported to lysosomes where the acid pH favors their dissociation from the receptors. Digestive enzymes lack the 6-phosphoryl mannose label, and are instead transported vectorially into a different secretory fraction. (3) Packaging of zymogens into maturing zymogen granules sequesters them from contact with other sub-cellular fractions. (4) Pancreatic secretory trypsin inhibitor (PSTI) is incorporated into the maturing zymogen granules. PSTI inactivates trypsin should there be any intra-acinar activation of trypsinogen. (5) Following stimulation (e.g., feeding and cholecystokinin secretion), mature zymogen granules and their contents are released from the cell into the ductal lumen in a process of membrane fusion and exocytosis. (6) Finally, zymogens are activated physiologically only after they enter the duodenum, where the brush border enzyme enteropeptidase activates trypsinogen, and trypsin then activates other pancreatic zymogen.52
A large body of experimental, and some clinical, evidence suggests that the initiating event of acute pancreatitis is the premature activation of digestive zymogens within the acinar cell.34,53-56 Premature activation of digestive zymogen results in acinar cell necrosis and pancreatic autodigestion. In acute pancreatic necrosis, protein synthesis and intracellular transport to the Golgi complex appear to be normal, but digestive zymogens then become co-localized along with lysosomal hydrolases in large vacuoles. Cell biology studies have revealed that lysosomal and zymogen granule fractions become co-localized through a process known as crinophagy, a process used by many cells to degrade accumulated secretory products when the need for secretion is no longer present. Although this process takes place in other cells without adverse consequences, it can be lethal in pancreatic acinar cells because of the peculiarity of their secretion products (digestive zymogens). Lysosomal hydrolases, such as cathepsin B and N-acetyl glucosaminidase, activate trypsinogen to the active trypsin form, and the enhanced fragility of these large vacuoles permits release of active enzyme into the cell cytoplasm. Trypsin acts auto-catalytically to activate other trypsinogen molecules and other zymogens, each inducing a unique chemical pathology in pancreatic and extra-pancreatic cells. A variety of inflammatory mediators and cytokines, interleukins, nitric oxide, and free radicals are involved in the further evolution of pancreatic acinar cell necrosis and inflammation and often determine the outcome.52,57-60 Thus, a bout of pancreatitis begins with an initiating event, e.g., ischemia, inflammation, or ductal obstruction, followed by acinar events, i.e., co-localization, enzyme activation, and cell injury, the outcome of which is influenced by severity determinants, e.g., inflammatory cytokines, reactive oxygen species, altered redox state, and apoptosis.59 The further evolution of acute pancreatic necrosis to a systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) is determined by the balance of pro-inflammatory and anti-inflammatory cytokines.60
History - Siamese cats were initially reported to be at increased risk for the disease in one of the first retrospective studies of feline pancreatitis.2 Clinical case surveys of the past 10 years suggest that most cases of feline pancreatitis are seen in the Domestic Short Hair breed.1-10 Anorexia (87%) and lethargy (81%) are the most frequently reported clinical signs in cats with acute pancreatitis, but these clinical signs are not pathognomonic for pancreatitis. Anorexia and lethargy are the most important clinical signs in many feline diseases. Gastroenterologic signs are sporadic and less frequently reported in the cat. Vomiting and diarrhea are reported in only 46% and 12% of cases, respectively,2-7,9,10 In dogs, vomiting (90%) and diarrhea (33%) appear to be more important clinical signs.12,27,49
Physical Examination Findings - Physical examination findings in cats with acute necrotizing pancreatitis include dehydration (54%), hypothermia (46%), icterus (37%), fever (25%), abdominal pain (19%), and abdominal mass (11%).2-7,9,10 These findings suggest that a "classic textbook" description of acute pancreatitis (e.g. vomiting, diarrhea, abdominal pain, and fever) is not consistently seen in the domestic cat. Many of these physical examination findings are more commonly reported in canine acute pancreatitis. Abdominal pain (58% in dogs; 19% in cats) and fever (32% in dogs; 25% in cats), for example, are more commonly reported in dogs with acute pancreatitis.12,27,49
The major differential diagnoses for feline acute necrotizing pancreatitis include gastrointestinal foreign body, inflammatory bowel disease, infectious gastroenteritis, gastrointestinal intussusception and neoplasia, cholangitis, biliary tract neoplasia, and various forms of liver pathology.
As with the same condition in the dog, diagnosis of acute necrotizing pancreatitis requires the careful integration of historical, physical examination, clinicopathologic, and imaging findings. Where appropriate, additional diagnostic support may be obtained at the time of laparoscopy or exploratory laparotomy. Diagnosis should not be made on the basis of a single laboratory or imaging finding.
In cats affected with acute necrotizing pancreatitis, laboratory abnormalities have included: normocytic, normochromic, regenerative or non-regenerative anemia (38%), leukocytosis (46%), leukopenia (15%), hyperbilirubinemia (58%), hypercholesterolemia (72%), hyperglycemia (45%), hypocalcemia (65%), hypoalbuminemia (36%), and elevations in serum alanine aminotransferase (57%) and alkaline phosphatase (49%) activities.2-7,9,10 Changes in red blood cell counts, serum activities of liver enzymes, and serum concentrations of bilirubin, glucose, and cholesterol are fairly consistent findings in feline acute necrotizing pancreatitis, just as they are in dogs.12,27,49 Important differences between cats and dogs appear to be reflected in white blood cell counts and serum calcium concentrations. Leukocytosis is a more important clinical finding in the dog (62% in dogs; 46% in cats).12,27,49 Leukopenia is sometimes seen instead of leukocytosis in cats, and a worse prognosis has been attributed to leukopenia in the cat.2,5,7,10 Hypocalcemia also appears to be a more frequent finding in cats (3-5 % in dogs12,49; 45-65% in cats2,5,6,10). Hypocalcemia (total and serum ionized) may result from several mechanisms, including acid-base disturbances, peripancreatic fat saponification, and parathormone resistance.61 Regardless of the mechanism, hypocalcemia appears to confer a worse clinical prognosis in cats.6,10 This finding suggests that cats should be monitored fairly closely for the development of hypocalcemia and treatment should be initiated, accordingly.
Special Tests of Pancreatic Function
Lipase and Amylase Activity Assays - Serum lipase activities are elevated in experimental feline pancreatitis,62,63 but serum lipase and amylase activities do not appear to be elevated or of clinical value in the diagnosis of clinical pancreatitis.a Serum lipase activity may still have some clinical utility in the diagnosis of acute necrotizing pancreatitis in the dog.12,64 Assays of serum lipase activity are complicated by the fact that there may be as many as five different isoenzymes circulating in the blood,65 consequently general serum lipase activity assays have been superseded by the development of pancreatic lipase immunoreactivity assays (e.g., cPLI, fPLI).65,66
Trypsin-like Immunoreactivity (TLI) - Serum TLI mainly measures trypsinogen but also detects trypsin and some trypsin molecules bound to proteinase inhibitors.66 TLI assays are species-specific, and different assays for feline (fTLI) and canine (cTLI) have been developed and validated.67 Serum TLI concentration is the diagnostic test of choice for feline exocrine pancreatic insufficiency because it is highly sensitive and specific for this disease in the cat.11 The use of this test in the diagnosis of feline acute necrotizing pancreatitis is less clear. Serum trypsinogen-like immunoreactivity (TLI) concentrations are transiently elevated in experimental feline acute pancreatitis,b but elevations in clinical cases are less consistently seen.a,5,7 The poor sensitivity (i.e., 33%) of this test precludes its use as a definitive assay for feline acute necrotizing pancreatitis.
Trypsinogen Activation Peptide (TAP) - When trypsinogen is activated to trypsin, a small peptide, TAP, is split from the trypsinogen molecule. Under normal conditions, activation of trypsinogen takes place only in the small intestine and TAP is undetectable in the blood. During pancreatitis, trypsinogen is activated prematurely in pancreatic acinar cells and TAP is released into the vascular space.66 Urine TAP assays have shown some promise in experimental models of feline pancreatitis,68 whereas serum TAP assays have shown some utility in preliminary clinical studies.c Large clinical trials will be required to determine the true specificity and sensitivity of this assay.
Pancreatic Lipase Immunoreactivity (PLI) - A radioimmunoassay for the measurement of pancreatic lipase immunoreactivity (fPLI) has been developed and validated in the cat.69 fPLI elevations have been cited in preliminary reports of experimentalb and clinicald feline acute necrotizing pancreatitis. Multi-institutional prospective clinical studies will be required to determine the true sensitivity and specificity of fPLI in the diagnosis of feline ANP.
Radiography - The radiographic findings of feline acute necrotizing pancreatitis have not been very well characterized. The radiographic hallmarks of canine acute pancreatitis (e.g. increased density in the right cranial abdominal quadrant, left gastric displacement, right duodenal displacement, and gas-filled duodenum/colon)12,70 have not been substantiated in the cat. Indeed, in several recent reports, many of these radiographic findings were not reported in cats with documented acute pancreatic necrosis.1-10 In spontaneous clinical cases, hepatomegaly and abdominal effusion appear to be the only radiographic findings associated with feline APN.1-10
Ultrasonography - Enlarged, irregular, and/or hypoechoic pancreas, hyperechogenicity of the peripancreatic mesentery, and peritoneal effusion have been observed with abdominal ultrasonography in many cats with spontaneous acute pancreatitis.3-8,10 The specificity of this imaging modality appears to be high (>85%), but the sensitivity has been reported as low as 35% in some studies.5,7,8 The low sensitivity suggests that imaging the pancreas in cats with pancreatitis is technically more difficult than imaging the pancreas in dogs or that the ultrasonographic appearance of pancreatitis in cats differs from that reported for dogs. New diagnostic criteria may be needed if abdominal ultrasonography is to be a more effective tool in the diagnosis of pancreatitis in cats.8,71
Computed Tomography - CT scanning appears to be useful in identifying the normal structures of the healthy feline pancreas,72 but preliminary clinical reports have been somewhat disappointing.d,7 The sensitivity of CT scanning in detecting lesions consistent with feline acute necrotizing pancreatitis may be as low as 20%.d,7 Additional study will be needed to determine the specificity and sensitivity of this imaging modality in the diagnosis of feline acute necrotizing pancreatitis.
If clinically indicated, pancreatic biopsy may be obtained by laparoscopy or exploratory laparotomy. Clinicians should always bear in mind that many pancreatitis patients are poor anesthetic risks. Gross observation at the time of laparoscopy or exploratory laparotomy may confirm the diagnosis of acute necrotizing pancreatitis. In equivocal cases, biopsy may be safely performed as long as blood flow is preserved at the site of the biopsy. Single biopsy may be insufficient to exclude subclinical pancreatitis as inflammation of the canine pancreas has been shown to occur in discrete areas within the pancreas rather than diffusely throughout the whole organ.73 Similar findings have been reported in feline acute necrotizing pancreatitis.2 Inspection of other viscera (e.g., intestine, biliary tract, liver) at the time of laparoscopy or exploratory laparotomy is of paramount importance in the cat because of the high rate of disease concurrence in this species.2,3,9,10,14,20,21
There are many important species differences between dogs and cats with regard to the clinical course and pathophysiology of acute pancreatic necrosis (summarized in reference 27). Fever, leukocytosis, vomiting, and abdominal pain are important physical examination findings in dogs with acute necrotizing pancreatitis, but these are relatively infrequent findings in cats with ANP. Cats more often have hypothermic reactions, and they may not necessarily manifest the classic gastroenterologic signs (e.g., vomiting, diarrhea, abdominal pain) reported in dogs. The imaging findings in cats are also less subtle than what has been reported in dogs; the classic radiographic hallmarks of canine ANP have not reported in the cat. Cats have a greater incidence and severity of hypocalcemia following bouts of acute pancreatic necrosis. Serum total and/or ionized hypocalcemia is significantly reduced in 45-65% of affected cats, whereas hypocalcemia is reported in only 5% of affected dogs. The pathogenesis of hypocalcemia in cats with ANP is incompletely understood, but it does carry a significantly worse prognosis for recovery.6 Prior gastrointestinal tract disease confers slight increased risk for the development of acute pancreatic necrosis in the dog;12,49 this is especially true of the cat.2,10,14,20,21
Supportive care continues to be the mainstay of therapy for feline acute pancreatitis. Efforts should be made to identify and eliminate any inciting agents, sustain blood and plasma volume, correct acid/base, electrolyte, and fluid deficits, place the pancreas in physiologic rest (NPO) for short periods of time, and treat any complications that might develop. Important life-threatening complications of acute pancreatitis in cats include hypocalcemia, disseminated intravascular coagulation, thromboembolism, cardiac arrhythmia, sepsis, acute tubular necrosis, pulmonary edema and pleural effusion.
Historically, a short period of fasting of food and water has been recommended for cats with acute necrotizing pancreatitis. This recommendation should be applied only in those cats in which there is severe vomiting and risk for aspiration pneumonia. As obligate carnivores, cats develop fat mobilization and hepatic lipidosis during prolonged starvation. Moreover, recent studies suggest that it may be appropriate and necessary to stimulate pancreatic secretion (via feeding) in affected animals.53-56 Esophagostomy, gastrostomy, and enterostomy tubes may be placed to facilitate nutrition in anorectic animals.
Other therapies that may be of some benefit in the treatment of this disorder include:
Relief of pain - Analgesic agents should be used when abdominal pain is suspected. Most cats do not manifest clinical signs of abdominal pain, but clinicians should be suspicious for it. Meperidine at a dose of 1-2 mg/kg administered intramuscularly or subcutaneously every 2-4 hours or butorphanol at a dose of 0.2-0.4 mg/kg administered subcutaneously every 6 hours have been recommended.74
Anti-emetic agents - Nausea and vomiting may be severe in affected animals. The ?2 adrenergic antagonists and 5-HT3 antagonists appear to be the most effective anti-emetic agents in the cat.75 Cats may be treated with chlorpromazine (?2 adrenergic antagonist) at a dose of 0.2-0.4 mg/kg administered subcutaneously or intramuscularly every 8 hours, or with any of the 5-HT3 antagonists (ondansetron 0.1-1.0 mg/kg, granisetron 0.1-0.5 mg/kg, or dolasetron 0.5-1.0 mg/kg, orally or intravenously every 12-24 hours). Dopaminergic antagonists, e.g., metoclopramide, are less effective anti-emetic agents in the cat.75
Calcium gluconate supplementation - Hypocalcemia is a frequent complication of feline acute necrotizing pancreatitis and is associated with a worse prognosis.6 Calcium gluconate should be given at doses of 50-150 mg/kg intravenously over 12-24 hours and serum total or ionized calcium concentrations should be monitored during therapy.
H1 and H2 histamine antagonists - Histamine and bradykinin-induced increases in microvascular permeability are associated with the development of hemorrhagic necrosis in experimental feline pancreatitis.76 Treatment with H1 (mepyramine, 10 mg/kg) and H2 (cimetidine, 5.0 mg/kg) histamine receptor antagonists protects against the development of hemorrhagic pancreatitis in these models.76 Efficacy has not been established in clinical pancreatitis, but the use of these drugs in suspected or proven clinical cases would seem to make sense since they are associated with few side effects. Diphenydramine (2-4 mg/kg) or dimenhydrinate (4-8 mg/kg) are examples of clinically used H1 histamine receptor antagonsists. Cimetidine (5.0 mg/kg), ranitidine (1.0-2.0 mg/kg), famotidine (0.5-1.0 mg/kg), and nizatidine (2.5-5.0 mg/kg) are examples of clinically used H2 histamine receptor antagonists.
Low dose dopamine infusion - Low dose dopamine infusion (5 ?g/kg/min) improves pancreatic blood flow and reduces microvascular permeability in feline experimental pancreatitis.63 Low dose dopamine infusion is effective treatment in experimental pancreatitis even when it is given up to 12 hours after induction of the disease.63 Part of the appeal of dopamine as a potential treatment for feline pancreatitis lies in the diversity of its actions. Dopamine's effect on the kidney in promoting renal blood flow and urinary output, and its cardiac inotropic effect make it an ideal agent, although it has not yet been studied in controlled clinical trials.
Broad spectrum antibiotics - Acute necrotizing pancreatitis may begin as a sterile process, but necrosis and inflammation predispose to colonic bacterial translocation and colonization of the pancreas.77,78 E. coli and other coliforms are the principal pathogens.77,78 High colonization rates suggest that bacteria may spread to the inflamed pancreas more frequently than is currently thought, and that broad spectrum antibiotics may be appropriate in suspected cases of feline acute pancreatitis. Cefotaxime at a dose of 50 mg/kg administered intramuscularly every eight hours prevents bacterial colonization of the pancreas.79
Ductal decompression - Surgical decompression of the pancreaticobiliary duct should be considered in cases of acute ductal obstruction, e.g., calculus, neoplasia, and fluke infection. Ductal decompression may also be useful in acute cases that have progressed to the more chronic form of the disease. Ductal decompression has been shown to restore pancreatic blood flow, tissue pH, and acinar cell function.31,32
In cases in which inflammatory bowel disease is the underlying pathogenesis of acute necrotizing pancreatitis, therapy should be directed toward regulation of the IBD. The five components of feline IBD therapy are dietary modification, antibiotics, probiotics, anti-diarrheal agents, and immunosuppressive therapy.80
Complications of Acute Necrotizing Pancreatitis - Chronic Non-Suppurative Pancreatitis
Recurring bouts of acute necrotizing pancreatitis may progress to a chronic non-suppurative form of the disease. This chronic form of pancreatitis has generally been held to be of lesser clinical severity, lower mortality, and better long term prognosis.1 More recent reports suggest however that chronic pancreatitis cannot be differentiated from acute pancreatitis by clinical, clinicopathologic, or imaging findings.10 The clinical signs, laboratory data, and imaging findings are indistinguishable between the two groups. Histopathology remains the only dependable method of differentiating acute and chronic pancreatitis. Not surprisingly, cats with chronic pancreatitis more frequently have concurrent systemic disease (e.g., cholangitis, IBD) compared to cats with acute pancreatitis.10
Complications of Acute Necrotizing Pancreatitis - Exocrine Pancreatic Insufficiency (EPI)
Exocrine pancreatic insufficiency (EPI) is an uncommon cause of chronic diarrhea in cats. Insufficiency results from failure of synthesis and secretion of pancreatic digestive enzymes. The natural history of feline exocrine pancreatic insufficiency is poorly understood, but most cases are believed to result from chronic pancreatitis, fibrosis, and acinar atrophy. As with dogs, clinical signs reported in cats with EPI include weight loss, soft voluminous feces, and ravenous appetite. Affected cats may have an antecedent history of recurring bouts of acute pancreatitis (e.g., anorexia, lethargy, vomiting) culminating in chronic pancreatitis and EPI.
The diagnosis of EPI in cats has been technically difficult. Clinical signs in affected cats are not pathognomonic for EPI, clinicopathologic data are fairly non-specific, imaging findings are inconsistent, and the severity of pancreatic histologic changes are not always directly related to the severity of clinical signs. One study suggests that serum TLI may be useful in the diagnosis of this disease.11 In that study, TLI concentrations less than 8 ?g/L (reference range = 17-49 ?g/L) were reported in 17/20 cats with clinical signs compatible with EPI (e.g., weight loss, loose voluminous feces, greasy soiling of the hair coat) and at least one other finding, e.g., decreased fecal proteolytic activity, exploratory laparotomy or necropsy findings compatible with EPI, or favorable response to pancreatic enzyme replacement therapy. Cats affected with EPI have predictable serum cobalamin deficiency because of pancreatic intrinsic factor deficiency and cobalamin malabsorption.81 Therapy should include subcutaneous vitamin B12 injections (100 µg subcutaneously every 3-4 weeks) in addition to pancreatic replacement enzymes.
Complications of Acute Necrotizing Pancreatitis - Hepatic Lipidosis
Acute necrotizing pancreatitis is but one of many examples in which anorexia or starvation predisposes an obligate carnivore to the syndrome of fat mobilization and hepatic lipidosis.1,3,82 The concurrence of these two syndromes is a particularly poor prognostic sign in that affected cats have high morbidity and mortality rates. This emphasizes the importance of early interventions in the treatment of pancreatitis before the development of the metabolic syndrome of hepatic lipidosis.
Complications of Acute Necrotizing Pancreatitis - Diabetes Mellitus
Several studies have related severe chronic pancreatitis to the development of diabetes mellitus.1,4,10,11 Acute necrotizing pancreatitis per se may not necessarily be a risk factor for the development of diabetes mellitus, but disease progression to the chronic non-suppurative form may increase that risk.
a) Parent C, Washabau RJ, Williams DA, et al. Serum trypsin-like immunoreactivity, amylase and lipase in the diagnosis of feline acute pancreatitis. Journal of Veterinary Internal Medicine 1995; 9: 194.
b) Williams DA, Steiner JM, Ruaux CG, Zavros N. Increases in serum pancreatic lipase immunoreactivity (PLI) are greater and of longer duration than those of trypsin-like immunoreactivity (TLI) in cats with experimental pancreatitis. Journal of Veterinary Internal Medicine 2003; 17: 445.
c) Allen H, Broussard J, Steiner JM, Mansfield CS, Williams DA. Comparison of clinical utility of different serum and urinary markers for feline pancreatitis. Journal of Veterinary Internal Medicine 2003; 17: 411.
d) Forman MA, Marks SL, DeCock HE, Hergesell ES, Wisner ER, Bakter T, Steiner JM, Williams DA. Evaluation of feline pancreatic lipase immunoreactivity and helical computed tomography versus conventional testing for the diagnosis of feline pancreatitis. Journal of Veterinary Internal Medicine 2003; 17: 411.
G.I. Motility Disorders: What's New in Diagnosis and Therapy
Canine Idiopathic Megaesophagus
Etiology - Idiopathic megaesophagus is the most common cause of regurgitation in the dog. The disorder is characterized by esophageal hypomotility and dilation, progressive regurgitation, and loss of body condition. Several forms of the syndrome have been described, including congenital idiopathic, acquired secondary, and acquired idiopathic megaesophagus.
Congenital idiopathic megaesophagus is a generalized hypomotility and dilation of the esophagus causing regurgitation and failure to thrive in puppies shortly after weaning. An increased breed incidence has been reported in the Irish setter, Great Dane, German shepherd, Labrador retriever, Chinese Shar-Pei, and Newfoundland breeds, and autosomal dominant inheritance has been demonstrated in the Miniature Schnauzer and Fox terrier breeds. 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. Congenital idiopathic megaesophagus has been reported in several cats, and in one group of cats secondary to pyloric dysfunction.
Acquired secondary megaesophagus may develop in association with a number of other conditions. Myasthenia gravis accounts for 25-30% of the secondary cases. 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. Hypothyroidism has been suggested as a secondary cause of idiopathic megaesophagus but retrospective risk factor analysis has not identified it as an important cause.
Most cases of adult-onset megaesophagus have no known etiology and are referred to as acquired idiopathic megaesophagus. The syndrome occurs spontaneously in adult dogs between 7 to 15 years of age without sex or breed predilection. The disorder has been compared erroneously to esophageal achalasia in humans. Achalasia is a failure of relaxation of the lower esophageal sphincter and ineffective peristalsis of the esophageal body. A similar disorder has never been rigorously documented in the dog. Several important differences between idiopathic megaesophagus in the dog and achalasia in humans have been documented. Although the etiology(ies) has not 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.
Routine hematology, serum biochemistry, and urinalysis should be performed in all cases to investigate possible secondary causes of megaesophagus (e.g. hypoadrenocorticism). Survey radiographs will be diagnostic for most cases of megaesophagus. 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.
If acquired secondary megaesophagus is suspected, additional diagnostic tests should be considered, for example: serology for nicotinic acetylcholine receptor antibody, ACTH stimulation, serology for antinuclear antibody, serum creatine phosphokinase activity, electromyography and nerve conduction velocity, and muscle and nerve biopsy. 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. Thyroid function testing (e.g., TSH assay, TSH stimulation, free and total thyroid hormones) should be performed in individual suspicious cases.
Treatment: Animals with secondary acquired megaesophagus should be appropriately differentiated from other esophageal disorders and treated. Dogs affected with myasthenia gravis should be treated with pyridostigmine (1.0-3.0 mg/kg PO BID) and/or corticosteroids (prednisone 1.0-2.0 mg/kg PO or SQ BID), dogs affected with hypothyroidism should be treated with levothyroxine (22 g/kg PO BID), and dogs affected with polymyositis should be treated with prednisone (1.0-2.0 mg/kg PO 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 non-peristaltic 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 esophageal peristalsis in affected animals, however metoclopramide and cisapride will not likely have much of an effect on the striated muscle of the canine esophageal body. Bethanechol 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. Because of the high incidence of esophagitis in canine idiopathic megaesophagus, affected animals should also be medicated with oral sucralfate suspensions (1 g q8h for large dogs 0.5 g q 8h for smaller dogs 0.25 to 0.5 g q8h to q12h for cats).
Prognosis: Animals with congenital idiopathic megaesophagus have a fair prognosis. With adequate attention to caloric needs and 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.
Gastric Emptying Disorders
Gastric emptying disorders are fairly common in dogs and cats. They result from disease processes that alter normal gastric functions, i.e. storage of ingesta, mixing and dispersion of food particles, and timely emptying of gastric contents into the small intestine. Disorders of gastric emptying arise from mechanical obstruction, or from defective propulsion. Anatomic lesions (e.g. malignancy, hyperplasia, foreign bodies) cause delayed gastric emptying because of mechanical obstruction. Diagnosis and management of mechanical obstruction is usually straight-forward. Disorders of defective propulsion, on the other hand, cause delayed gastric emptying because of abnormalities in myenteric neuronal or gastric smooth muscle function, or because of abnormalities in antropyloroduodenal coordination. A number of primary conditions have been associated with these functional disorders, including infectious or inflammatory disease, ulcer, and post-surgical gastroparesis. Delayed gastric emptying has also been associated with a number of secondary conditions, including electrolyte disturbances, metabolic disorders, concurrent drug usage (cholinergic antagonists, adrenergic agonists, opioid agonists), acute stress, and acute abdominal inflammation. Recovery from gastric dilation/volvulus is almost always associated with significant myoelectrical and motor abnormalities in the dog. Diagnosis and management of the delayed gastric emptying disorders may not be so straight-forward. Nutritional and medical management, including smooth muscle prokinetic agents (e.g., cisapride, erythromycin, and ranitidine), are important components of therapy.
Small Intestinal Transit Disorders
A number of small intestinal transit disorders have been described in dogs and cats, including enteritis, post-surgical pseudo-obstruction, nematode infection, intestinal sclerosis, and radiation enteritis. Vomiting and diarrhea are the most important clinical signs associated with these disorders. Overgrowth of small intestinal bacteria, a common sequela to disordered motility, contributes to these clinical signs. Transit disorders associated with mechanical obstruction should always be differentiated and treated appropriately. Delayed transit associated with functional disorders should be managed with dietary modification (low fat diets) and prokinetic agents (cisapride, tegaserod, or metoclopramide). Tegaserod, a new 5-HT4 partial agonist, has recently been reported to normalize intestinal transit in opioid-induced bowel dysfunction in dogs.
Colonic Motility Disorders
History: Constipation, obstipation, and megacolon may be observed in cats of any age, sex, or breed, however, most cases are observed in middle aged (mean = 5.8 years), male cats (70% male, 30% female) of Domestic Shorthair (46%), Domestic Longhair (15%), or Siamese (12%) breeding. Affected cats are usually presented for reduced, absent, or painful defecation for a period of time ranging from days to weeks or months. Some cats are observed making multiple, unproductive attempts to defecate in the litter box, while other cats may sit in the litter box for prolonged periods of time without assuming a defecation posture. Dry, hardened feces are observed inside and outside of the litter box. Occasionally, chronically constipated cats have intermittent episodes of hematochezia or diarrhea due to the mucosal irritant effect of dehydrated feces.
Physical Examination: Colonic impaction is a consistent physical examination finding in affected cats. Other findings will depend upon the severity and pathogenesis of constipation. Dehydration, weight loss, debilitation, abdominal pain, and mild to moderate mesenteric lymphadenopathy may be observed in cats with severe idiopathic megacolon. Colonic impaction may be so severe in such cases as to render it difficult to differentiate impaction from colonic, mesenteric, or other abdominal neoplasia. Cats with constipation due to dysautonomia may have other signs of autonomic nervous system failure, such as urinary and fecal incontinence, regurgitation due to megaesophagus, mydriasis, decreased lacrimation, prolapse of the nictitating membrane, and bradycardia. Digital rectal examination should be carefully performed with sedation or anesthesia especially in those cats with recurring bouts of constipation. Pelvic fracture malunion may be detected on rectal examination in cats with pelvic trauma. Rectal examination might also identify other unusual causes of constipation, such as foreign bodies, rectal diverticula, stricture, inflammation, or neoplasia. Chronic tenesmus may be associated with perineal herniation in some cases. A complete neurologic examination with special emphasis on caudal spinal cord function should be performed to identify neurologic causes of constipation, e.g. spinal cord injury, pelvic nerve trauma, and Manx sacral spinal cord deformity.
Several authors have emphasized the importance of considering an extensive list of differential diagnoses (e.g. neuromuscular, mechanical, inflammatory, metabolic/endocrine, pharmacologic, environmental, and behavioral causes) for the obstipated cat. A review of published cases, however, suggests that 96% of cases of obstipation are accounted for by idiopathic megacolon (62%), pelvic canal stenosis (23%), nerve injury (6%), or Manx sacral spinal cord deformity (5%). A smaller number of cases are accounted for by complications of colopexy (1%) and colonic neoplasia (1%); colonic hypo- or aganglionosis was suspected, but not proved, in another 2% of cases. Inflammatory, pharmacologic, and environmental/behavioral causes were not cited as predisposing factors in any of the original case reports. Endocrine factors (obesity, n=5; hypothyroidism, n=1) were cited in several cases, but were not necessarily impugned as part of the pathogenesis of megacolon.
The pathogenesis of idiopathic megacolon has been historically attributed to a primary neurogenic or degenerative neuromuscular disorder. While it seems clear that a small number of cases (11%) result from neurologic disease, the vast majority (>90%) of cases have no evidence of neurologic disease. Some of the idiopathic cases may instead involve disturbances of colonic smooth muscle as suggested by several studies. In vitro isometric stress measurments were performed on colonic smooth muscle segments obtained from cats suffering from idiopathic dilated megacolon. These studies suggested that the disorder of feline idiopathic megacolon is a generalized dysfunction of colonic smooth muscle, and that treatments aimed at stimulating colonic smooth muscle contraction might improve colonic motility.
The specific therapeutic plan will depend upon the severity of constipation and the underlying cause. Medical therapy may not be necessary with first episodes of constipation. First episodes are often transient and resolve without therapy. Affected animals should always be re-hydrated if dehydration has contributed to the onset of clinical signs. Mild to moderate or recurrent episodes of constipation usually require some medical intervention. These cases may be managed, often on an outpatient basis, with dietary modification, water enemas, oral or suppository laxatives, and/or colonic prokinetic agents. Severe cases of constipation usually require brief periods of hospitalization to correct metabolic abnormalities and to evacuate impacted feces using water enemas, manual extraction of retained feces, or both. Followup therapy in such cases is directed at correcting predisposing factors and preventing recurrence. Subtotal colectomy will become necessary in cats suffering from obstipation or idiopathic dilated megacolon. These cats, by definition, are unresponsive to medical therapy. Pelvic osteotomy without colectomy may be sufficient for some cats suffering from pelvic canal stenosis and hypertrophic megacolon.
NEW DEVELOPMENTS IN PROKINETIC THERAPY
Cisapride (Janssen Pharmaceutical)
Cisapride was widely used in the management of canine and feline gastric emptying, intestinal transit, and colonic motility disorders throughout most of the 1990's. Cisapride was withdrawn from the American, Canadian and certain Western European in July of 2000 following reports of untoward cardiac side effects in human patients. Cisapride causes QT interval prolongation and slowing of cardiac repolarization via blockade of the rapid component of the delayed rectifier potassium channel (IKr). This effect may result in a fatal ventricular arrhythmia referred to as torsades de pointes. Similar effects have been characterized in canine cardiac Purkinje fibers, but in vivo effects have not yet 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 throughout the United States. Two new prokinetic agents, prucalopride and tegaserod, are in differing stages of drug development and may prove useful in the therapy of G.I. motility disorders of several animal (dog, cat, horse) species.
Tegaserod (SDZ HTF 919 - Novartis Corporation)
Tegaserod is a potent partial non-benzamide agonist at 5-HT4 receptors and a weak agonist at 5-HT1D receptors. Tegaserod has definite prokinetic effects in the canine colon. Intravenous doses of tegaserod (0.03-0.3 mg/kg) accelerate colonic transit in dogs during the first hour after intravenous administration. The highest doses of tegaserod (0.1 and 0.3 mg/kg) have no greater efficacy than lower doses (0.03 mg/kg), suggesting the possibility that tegaserod may stimulate canine colonic motility through a receptor-independent mechanism, or that tegaserod may act at sites other than 5-HT4 receptors at higher doses.
The motor mechanisms responsible for tegaserod-induced canine colonic propulsion are unclear. High amplitude propagated phasic contractions are thought to be responsible for mass movements, but they were not observed during tegaserod infusion. Contraction, amplitude, and motility indices were not different postprandially among treatment groups, so the mechanism of the tegaserod effect will require more detailed investigation in the dog.
In vitro studies suggest that tegaserod does not prolong the QT interval or delay cardiac repolarization as has been occasionally reported with cisapride.
Clinical efficacy has been demonstrated in human motility disorders, and new drug approval was rewarded by the U.S. Food and Drug Administration in September 2002. Tegaserod has been marketed under the trade name of Zelnorm in the United States, and under the trade name of Zelmec in the United Kingdom.
Gastric effects of tegaserod have not been reported in the dog, so this drug may not prove as useful as cisapride in the treatment of delayed gastric emptying disorders. Tegaserod at doses of 3-6 mg/kg PO has been shown to normalize intestinal transit in opioid-induced bowel dysfunction in dogs, and it may be useful in other disorders of intestinal ileus or pseudo-obstruction.
Prucalopride (R093877 - Janssen Pharmaceutical)
Prucalopride is a potent partial benzamide agonist at 5-HT4 receptors, but is without effect on other 5-HT receptors or cholinesterase enzyme activity. Prucalopride dose-dependently (0.02-1.25 mg/kg) stimulates giant migrating contractions (GMC's) and defecation in the dog. 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. 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. 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 has not yet been marketed in the United States or elsewhere.
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. In vitro studies of misoprostol show that it stimulates feline and canine colonic smooth muscle contraction. Given its limited toxicity, misoprostol may be useful in dogs and cats with severe refractory constipation.
What Does the Future Hold for Companion Animal Prokinetic Therapy?
The 5-HT4 receptor appears to hold the most interest and promise for future drug development. 5-HT4 receptor activation can cause relaxation or contraction depending on the region, cell type, and animal species. In the dog, the effects of selective 5-HT4 receptor agonists suggest that these receptors are present on jejunal mucosa, ileal mucosa, gastric cholinergic neurons, and circular colonic smooth muscle cells. Increased motor activity following 5-HT4 receptor activation results from increased release of acetylcholine from cholinergic neurons, and relaxation results from 5-HT4 receptors on 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.