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Feline exocrine pancreatic disease: A diagnostic and therapeutic challenge (Proceedings)
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.
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, but other forms of biliary tract pathology (e.g., stricture, neoplasia, and calculus) have known associations. Epidemiologic studies 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. 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.
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. Several factors appear to contribute to this association: (1) High incidence of inflammatory bowel disease – IBD is a common disorder in the domestic cat. 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. 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, 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. Bacteria readily proliferate in the feline small intestine because of differences in gastrointestinal motility and immunology. 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.
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. Acidic metabolites accumulate within the pancreas because of impaired blood flow Ductal decompression has been shown to restore pancreatic blood flow, tissue pH, and acinar cell function.
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. 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.
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. The pancreas is readily colonized by Toxoplasma gondii organisms during the acute phase of infection. 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. Feline herpesvirus I and feline infectious peritonitis viruses have been implicated as causative agents in several case reports, and feline parvoviral infection has been associated with viral inclusion bodies and pancreatic acinar cell necrosis in young kittens. 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. 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. Caliciviral infection has not been reported in any of the recent clinical case series of feline acute necrotizing pancreatitis, 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. 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, and several cases have been reported in the cat. In one survey, several cats developed ANP following treatment for ectoparasites, and two cats developed ANP following treatment with fenthion. 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, 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. Moderate hypercalcemia was found as a pre-existing laboratory finding in 10% of the cases of fatal canine acute pancreatitis. Acute experimental hypercalcemia does indeed cause acute pancreatic necrosis and pancreatitis in cats, 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.
Nutrition – High fat feedings and obesity 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.
History - Siamese cats were initially reported to be at increased risk for the disease in one of the first retrospective studies of feline pancreatitis. Clinical case surveys of the past 10 years suggest that most cases of feline pancreatitis are seen in the Domestic Short Hair breed. 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. In dogs, vomiting (90%) and diarrhea (33%) appear to be more important clinical signs.
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%). 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.
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. 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. 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). Leukopenia is sometimes seen instead of leukocytosis in cats, and a worse prognosis has been attributed to leukopenia in the cat. Hypocalcemia also appears to be a more frequent finding in cats (3-5 % in dogs; 45-65% in cats). Hypocalcemia (total and serum ionized) may result from several mechanisms, including acid-base disturbances, peripancreatic fat saponification, and parathormone resistance. Regardless of the mechanism, hypocalcemia appears to confer a worse clinical prognosis in cats. 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, but serum lipase and amylase activities do not appear to be elevated or of clinical value in the diagnosis of clinical pancreatitis. Serum lipase activity may still have some clinical utility in the diagnosis of acute necrotizing pancreatitis in the dog. Assays of serum lipase activity are complicated by the fact that there may be as many as five different isoenzymes circulating in the blood, consequently general serum lipase activity assays have been superseded by the development of pancreatic lipase immunoreactivity assays (e.g., cPLI, fPLI).
Trypsin-like Immunoreactivity (TLI) – Serum TLI mainly measures trypsinogen but also detects trypsin and some trypsin molecules bound to proteinase inhibitors. TLI assays are species-specific, and different assays for feline (fTLI) and canine (cTLI) have been developed and validated. 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. 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, but elevations in clinical cases are less consistently seen. The poor sensitivity (i.e., 33%) of this test precludes its use as a definitive assay for feline acute necrotizing pancreatitis.
Pancreatic Lipase Immunoreactivity (PLI) – A radioimmunoassay for the measurement of pancreatic lipase immunoreactivity (fPLI) has been developed and validated in the cat. fPLI elevations have been cited in preliminary reports of experimental and clinical 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) 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. In spontaneous clinical cases, hepatomegaly and abdominal effusion appear to be the only radiographic findings associated with feline APN.
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. 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.
Computed Tomography – CT scanning appears to be useful in identifying the normal structures of the healthy feline pancreas, but preliminary clinical reports have been somewhat disappointing. The sensitivity of CT scanning in detecting lesions consistent with feline acute necrotizing pancreatitis may be as low as 20%. Additional study will be needed to determine the specificity and sensitivity of this imaging modality in the diagnosis of feline acute necrotizing pancreatitis.
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. 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.
- Anti-emetic agents – Nausea and vomiting may be severe in affected animals. The α2 adrenergic antagonists and 5-HT3 antagonists appear to be the most effective anti-emetic agents in the cat. Cats may be treated with chlorpromazine (α2 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. NK1 antagonists have not yet been studied in feline acute pancreatitis.
- Calcium gluconate supplementation – Hypocalcemia is a frequent complication of feline acute necrotizing pancreatitis and is associated with a worse prognosis. 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. 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. 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.
The reader is referred to: Washabau RJ. Feline acute necrotizing pancreatitis. In, August JR, ed. Consultations in Feline Internal Medicine. 5th ed. Philadelphia: WB Saunders Co., 2005, 109-116.