Feline pancreatitis (Proceedings)

Disorders of the feline exocrine pancreas are common. Feline pancreatitis is classified as acute necrotizing, acute suppurative and chronic non-suppurative1. Acute pancreatitis is characterized by inflammation of the pancreas that is completely reversible upon removal of the underlying cause, while chronic pancreatitis is characterised by irreversible histological lesions such as fibrosis and atrophy2. Necrosis of pancreatic acinar cells and peripancretic fat with or without inflammation, hemorrhage, mineralization and fibrosis, describes acute necrotizing pancreatitis (ANP) 1. Acute suppurative pancreatitis differs in that neutrophilic inflammation is the predominant histologic lesion1. Chronic pancreatitis (CP) is characterized by lymphocytic inflammation, fibrosis and pancreatic acinar actrophy1. ANP and CP are most common, are clinically indistinguishable in the absence of a pancreatic biopsy1 and will be the focus of this discussion.

Pathogenesis and Etiology

Digestive enzymes are stored within pancreatic acinar cells as inactive enzyme precursors or zymogens (e.g. trypsinogen). After release into the intestinal lumen, trypsinogen is cleaved by enterokinase (secreted by duodenal mucosal cells) to its active form trypsin. In turn, trypsin activates other zymogens. Pancreatitis is characterized by inappropriate activation of zymogens within the pancreatic parenchyma2,3. In most patients this is due to fusion of lysosomal and zymogen granules within the pancreas, conversion of trypsinogen to trypsin and subsequent intra-pancreatic activation of other zymogens2,3. Unlike dogs, the feline pancreatic duct and common bile duct merge before emptying into the duodenum at the common bile duct, predisposing cats to pancreatic inflammation secondary to reflux of intestinal or biliary contents. Following zymogen activation, free radical–associated damage and pancreatic edema due to increased capillary permeability occur. Pancreatic inflammation extends locally to the stomach, duodenum, colon and potentially the adjacent hepatic parenchyma. Enzyme leakage into the bloodstream can overwhelm circulating antiproteases and potentially lead to hypotension, shock, disseminated intravascular coagulopathy (DIC), multiple organ failure and death2,3. It has been speculated that ANP and CP may have similar etiologies and pathogenesis and could represent a continuum of disease1. Accepted etiologies of feline ANP include biliary tract disease (most notably suppurative cholangitis), inflammatory bowel disease, pancreatic ischemia (e.g. hypotension, consequence of severe inflammation and edema, etc.), pancreatic duct obstruction (e.g. neoplasia, pancreatic fluke, duodenal foreign body, etc.), blunt abdominal trauma, infection (e.g. Toxoplasma gondii), organophosphate toxicosis and lipodystrophy1. There is currently insufficient evidence to consider hypercalcemia, drug reactions, high fat diet or obesity as risk factors for development of feline pancreatitis1. In many cases, no specific pre-disposing factor or inciting cause is identified. However, concurrent hepatobiliary or intestinal tract disease is common.

Patient presentation

No age, gender or breed predispositions are recognized. Clinical signs of feline pancreatitis are often vague and non-specific. The most common clinical signs of feline pancreatitis, in descending order, are lethargy, inappetance / anorexia, dehydration, hypothermia, vomiting, weight loss, abdominal pain, palpable cranial abdominal mass, dyspnea (due to pain, pleural effusion, pulmonary thrombosis, etc.) and diarrhea4-6. Less frequent clinical signs include fever, icterus, polyuria, polydipsia and constipation2. ANP and CP can not be differentiated in cats on the basis of clinical signs, duration of clinical signs or physical exam findings5. However, the clinical impression of some is that the clinical signs of CP are milder than those of ANP. Clinical signs associated with underlying, predisposing or complicating conditions may also be observed. Physical exam findings reflect clinical signs and can include dehydration, pallor, icterus, hypo- or hyperthermia, tachypnea, hypersalivation, abdominal pain, hepatomegaly and palpable cranial abdominal mass1,5. Clinical signs reflective of concurrent conditions may also be noted.

The diagnosis of feline pancreatitis is not made on the basis of a single diagnostic test but rather through careful consideration of patient presentation and the results routine clinicopathological testing, specific tests of pancreatic function, diagnostic imaging and histopathology1.

Routine clinicopathological testing: Complete blood count findings are non-specific but have been reported to include mild to severe anemia (usually normocytic normochromic non-regenerative), leukocytosis or leukopenia, lymphopenia and neutrophilia4,5,7. The most frequently identified serum biochemical abnormalities are increased liver enzyme activities, hyperbilirubinemia and electrolyte abnormalities (hypokalemia, hypochloremia, low total serum and plasma ionized calcium concentration)3-5,7-9. Pre-renal azotemia, renal azotemia, hypoalbuminemia, hypercholesterolemia and hyper or hypoglycemia are also possible findings4,8. Serum ALT and ALP activities may be higher in cats with CP compared to cats with ANP5. Hypoalbuminemia may be more common among cats with moderate to severe pancreatitis than among cats with mild pancreatitis or among normal cats10. Serum amylase and lipase concentrations do not generally increase and as such are of no diagnostic value in naturally occurring feline pancreatitis11. Urinalysis is indicated as a component of the minimum database. Urine should be specifically evaluated for urine concentrating ability (distinguish pre-renal from renal azotemia), proteinuria, glucosuria and ketonuria (predisposing or complicating diabetes mellitus).

Specific Tests of Pancreatic Function

Feline trypsin-like immunoreactivity (fTLI) is a species specific assay that measures the combined serum concentration of trypsinogen, trypsin and some of the trypsin bound to proteinase inhibitors1. fTLI is the test of choice for diagnosis of feline exocrine pancreatic insufficiency and was evaluated for use in the diagnosis of feline pancreatitis on the assumption that increases in serum concentration would occur with pancreatic inflammation and leakage1,12. While fTLI is increased in some cats with pancreatic inflammation, significant overlap in fTLI concentrations between healthy cats and cats with pancreatic disease and the relative insensitivity of the test means it is not a definitive test 6,10,12,13. A normal fTLI does not rule out pancreatitis12. Feline pancreatic lipase immunoreactivity (fPLI) is a species specific assay that measures the circulating mass of pancreatic-origin lipase. Lipase as assayed on a serum biochemical profile measures the enzymatic activity of lipase from all sources (pancreatic, gastric duodenal)7. In one report, the sensitivity of fPLI for diagnosis of moderate to severe pancreatitis was high (100%) but was low (54%) for diagnosis of mild pancreatitis10 (N.B. disease severity was determined based on histopathology grading of pancreatic biopsies). Further, the specificity of the test was high in healthy cats (100%) but low (33%) in cats with similar clinical signs but normal pancreatic histology10. This data suggests fPLI testing should reliably diagnose pancreatitis in cats with moderate to severe disease but may have a high false negative rate in cats with mild disease and a high false positive rate in cats with similar clinical signs due to non-pancreatic disease. fPLI is the most sensitive single test currently available for diagnosis of feline pancreatitis.

Diagnostic Imaging

The sensitivity of plain abdominal radiographs for diagnosis of feline pancreatitis is very low8,12. Abdominal radiographs are indicated for evaluation of alternate or additional pathology but should not be expected to be diagnostic for pancreatitis. Radiographic abnormalities that have been reported in cats with pancreatitis are generally non-specific and include poor serosal detail suggestive of peritoneal effusion (most common), mass effect in the region of the pancreas and dilated loops of bowel4,5. The sensitivity of abdominal ultrasound alone for diagnosis of mild pancreatitis in cats is low (11-35%)6,12,14. However, the sensitivity of ultrasound for diagnosis of moderate to severe pancreatitis is higher (88%)10. Abdominal ultrasound findings are unremarkable in as many as 54% and 46% of cats with ANP or CP, respectively5,14. Further, the pancreas can not be reliably identified in some cats, even by expert ultrasonographers14. Pancreatic ultrasonographic abnormalities that have been reported in cats with pancreatitis include hyperechoic or hypoechoic pancreas, enlarged pancreas, hyperechoic peripancreatic mesentery and pancreatic mass effect6,14. Among the reported non-pancreatic ultrasonographic abnormalities are peritoneal effusion, hyperechoic liver, dilated bile ducts, thickened bowel wall and lymphadenomegaly6,14. Computed tomography (CT) imaging of the feline abdomen is not recommended for diagnosis of feline pancreatitis due to difficulty identifying the feline pancreas6 and lack of difference in CT measurements between normal cats and cats with pancreatitis10.

Histopathology

A definitive ante mortem diagnosis is obtained via histological evaluation of multiple (e.g. distal right and left limbs) pancreatic biopsies, obtained laprascopically or via exploratory laparotomy2,10. Inflammatory lesions may have a multifocal distribution so evaluation of multiple biopsies is recommended to maximize the likelihood of obtaining an accurate diagnosis2,10. In a clinical setting feline pancreatitis is generally diagnosed or suspected on the basis of clinical signs and combined results of the above described tests. While pancreatic biopsy alone is generally not sufficient indication for surgical or laparoscopic exploration of the abdomen, pancreatic biopsy should be considered if there is another indication for said procedure(s) (e.g. gastrointestinal biopsies, hepatobiliary biopsy and culture, gastrotomy or jejunostomy tube placement, etc.).

Fluid Therapy

Subcutaneous administration of an isotonic balanced electrolyte solution may be sufficient to correct mild fluid deficits (<5%) but is insufficient for patients with moderate to severe dehydration. In such cases, intravenous fluid therapy for correction of dehydration, replacement of ongoing fluid losses and provision of maintenance fluid requirements is indicated to stabilize the patient and avoid pancreatic ischemia7,12. In addition to initial serum electrolyte measurements, cats should be monitored frequently for hypokalemia (due to increased gastrointestinal losses (vomiting, diarrhea) and inadequate intake (partial or complete anorexia)) and supplemented appropriately.

Nutritional support

Traditional treatment of canine and human patients with pancreatitis generally involves withholding food and water to "rest" the pancreas by limiting pancreatic secretion which is stimulated by food and stomach acid in the duodenum7. However, given the tendency for feline patients to have a history of complete or partial anorexia prior to presentation and concerns over development of hepatic lipidosis, cats with pancreatitis that are not vomiting should be fed orally7 and can initially be enticed or encouraged to eat on their own. Enteral tube feeding (nasoesophageal, esophageal, gastrotomy or jejunostomy) must be considered for any cat that has been anorexic or has had inadequate voluntary caloric intake for more than 3 days, cats that have lost ≥ 10% of their body weight and cats with other overt signs of malnutrition such as poor hair coat, muscle wasting, poor wound healing, etc15. If the patient is vomiting, antiemetic therapy (see below) should be instituted and water followed by a maintenance or low carbohydrate diet re-introduced 12-24 hours after the last episode of vomiting7,12. If vomiting cannot be controlled in a cat that has gone without adequate oral intake for 3 or more days, placement of a jejunostomy tube (ideally) or total parenteral nutrition is indicated7.

Analgesia

Analgesic therapy is an important consideration in all cats with pancreatitis. The absence of overt signs of discomfort does not rule out abdominal pain in cats7,12. Opiods are logical first choices for analgesic therapy. Consider: buprenorphine (0.005-0.03 mg/kg IV, IM, SQ q6-12 hours), butorphanol (0.2-0.4 mg/kg IV, IM, SC q2-4 hours) or fentanyl (0.004-0.01 mg/kg IV bolus followed by 0.001-0.004

mg/kg/hr constant rate IV infusion OR 25 mcg/hr transdermal patch every 3-4 days)7,12,16.

Antibiotics

Antibiotics are not indicated in the treatment of isolated, uncomplicated feline pancreatitis. Antibiotic therapy may be considered if an infectious etiology (i.e. toxoplasmosis), systemic bacterial infection (left shift and/or toxic neutrophils, persistent fever, hypoglycemia, etc.) or concurrent antibiotic responsive condition (e.g. cholangiohepatitis) is suspected. Some authors have postulated that anorexia predisposes to disruption of the intestinal epithelial barrier and bacterial translocation with subsequent bacterial colonization of a necrotic pancreas1,12. Antibiotic choice will depend on the indication(s) for treatment. If treatment is initiated based on suspicion of gastrointestinal bacterial translocation, cefotaxime (50 mg/kg IV or IM q6 hours) or the combination of enrofloxacin (5 mg/kg IV or PO q24 hours) and ampicillin (22 mg/kg, IV, IM, or SQ, every 6-8 hours) will provide broad spectrum coverage and effectively penetrate pancreatic tissue1,7.

Antiemetics, Gastroprotectants, Appetite Stimulants

Clinical signs of nausea are not limited to vomiting and may include hypersalivation, bruxism, retching or anorexia. Antiemetic treatment options for feline patients include: metoclopramide (0.2-0.4 mg/kg PO, SQ, IV q8 hours or 1-2 mg/kg/24 hours CRI), ondansetron (0.1 mg/kg IV or PO q 12-24 hours), chlorpromazine (0.3-0.5 mg/kg SQ q8 hours) and maropitant (off-label use, 1 mg/kg PO or SQ q24 hours for 5 days)17. Chlorpromazine has been associated with development of extrapyramidal signs in cats and because of the risk of hypotension, chlorpromazine must only be used in well hydrated patients. It is suggested that α2-adrenergic antagonists (chlorpromazine) and 5-HT3 antagonists (ondansetron) are the most effective and doapminergic antagonists (metoclopramide) the least effective antiemetic agents in the cat1. If gastrointestinal ulceration is suspected, treatment with an H2 receptor antagonist (famotidine 0.5-1.0 mg/kg PO, SQ or slow IV q12 hours) or H2 receptor blocker (omeprazole 0.7-1.5 mg/kg PO q24 hours) is indicated16. Pharmacological stimulation of appetite in sick cats is generally unreliable, short-lived and may delay implementation of an enteral feeding plan15. It is the author's opinion that pharmacological stimulation of appetite is only indicated in the short term (i.e. days) for outpatients that are consuming >50% of their required calories voluntarily or in patients whose owners are not prepared to consent to feeding tube placement. Pharmacological stimulation of appetite should not be relied on or used in lieu of feeding tube placement. Appetite stimulants include cyprohepatadine (2-4 mg per cat PO q12-24 hours) or mirtazapine (1.875-3.75 mg per cat PO q72 hours)16. Side effects of cyproheptadine include behavioural changes (sedation or paradoxical hyperexcitability) and anticholinergic effects15,16. Side effects of mirtazapine include anecdotal reports of behaviour changes and hyperexcitability. Mirtazapine should not be used in combination with selective serotonin reuptake inhibitors (risk of serotonin syndrome) and should be used in caution in cats with hepatic disease15.

Cobalamin Supplementation

Cobalamin (±2) is a dietary, water-soluble, B vitamin. Bound to intrinsic factor, dietary cobalamin absorption occurs in the ileum. Cobalamin deficiency due to poor dietary absorption is common in cats with small intestinal disease or exocrine pancreatic insufficiency. Many laboratories combine measurement of cobalamin and folate levels with assessment of fPLI in a single panel. Dosing regimens for cobalamin supplementation in the cat have not been critically evaluated. One suggested regimen is: cyanocobalamin 150-250 µg per cat SQ q7 days for 6 weeks, then q14 days for 6 weeks, then q30 days for 1 injection followed by re-evaluation of serum cobalamin levels 1 month later18. Following this, serum cobalamin concentration should be above the reference range18. If it is within the reference range, supplementation is continued on a monthly basis and if it is below the reference range supplementation is continued on a weekly to biweekly basis and reconsideration of the suspected diagnosis and treatment protocol is recommended18.

Corticosteroids

Some cats with CP seemingly improve with corticosteroid therapy, leading to speculation of an immune-mediated pathogenesis7. Given the high incidence of concurrent gastrointestinal and hepatobiliary disease in cats with pancreatitis, the observed improvement may be due to resolution of a concurrent corticosteroid -responsive condition (e.g. IBD, lymphocytic cholangitis). While corticosteroids are indicated for treatment of a concurrent steroid responsive condition, there is insufficient evidence to recommend corticosteroid therapy for cats with CP.

Other: Additional therapeutic agents including low-dose dopamine infusion and H1 and H2 receptor antagonists have shown some benefit in an experimental model of feline pancreatitis1,7 but have yet to be evaluated in naturally occurring disease.

Complications and Prognosis

In addition to acute systemic complications such as hypotension, DIC, organ failure and death, specific complications of feline pancreatitis include progression to CP, hepatic lipidosis, pancreatic failure (i.e. exocrine pancreatic insufficiency or diabetes mellitus) and pancreatic pseucocysts, abscesses or necrosis1,8. Plasma ionized calcium concentration < 1.00 mmol/L or the presence of concurrent hepatic lipidosis are associated with a poor prognosis7-9. While it seems intuitive that cats with systemic complications or significant concurrent conditions have a poor prognosis, this has not been critically evaluated.

References

Washabau RJ. Feline Pancreatic Disease. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7th ed. St. Louis: Saunders Elsevier; 2010:1704-1711.

Williams DA. Feline exocrine pancreatic disease. In: Bonagura JD, Twedt DC, eds. Current Vaterinary Therapy XIV. St. Louis: Saunders Elsevier; 2009:538-543.

Whittemore and Campbell. Canine and Feline Pancreatitis. Comp Cont Ed Pract Vet 2006: 766-775.

Hill RC and Van Winkle TJ. Acute necrotizing and acute suppurative pancreatitis in the cat: A retrospective study of 40 cases (1976-1989). JVIM 1993: 7; 25-33.

Ferreri JA, et al., Clinical differentiation of acute necrotizing from chronic nonsuppurative pancreatitis in cats: 63 cases (1996-2001). JAVMA 2003;223:469–474.

Gerhardt A, et al., Comparison of the sensitivity of different diagnostic tests for pancreatitis in cats. JVIM 2001; 15: 329-333.

Xenoulis PG, et al., Current concepts in feline pancreatitis. Topics in Companion Animal Medicine 2008; 23(4): 185-192.

Xenoulis PG, et al., Chronic pancreatitis in dogs and cats. Comp Cont Ed Pract Vet 2008: 166-181.

Kimmel SE., et al. Incidence and prognostic value of low plasma ionized calcium concentration in cats with acute pancreatitis: 46 cases (1996-1998). JAVMA 2001;219:1105–1109.

Forman MA, et al., Evaluation of Serum Feline Pancreatic Lipase Immunoreactivity and Helical Computed Tomography versus Conventional Testing for the Diagnosis of Feline Pancreatitis. JVIM 2004; 18: 807-815.

Parent C, et al., Trypsin-like immunoreactivity, amylase and lipase in the diagnosis of feline acute pancreatitis. 1995. JVIM abstract.

Zoran DL. Pancreatitis in cats: Diagnosis and management of a challenging disease. JAAHA 2006; 42: 1-9.

Swift NC, et al., Evaluation of serum feline trypsin-like immunoreactivity for the diagnosis of pancreatitis in cats. JAVMA 2000;217:37–42.

Saunders HM, et al. Ultrasonographic findings in cats with clinical, gross pathologic and histologic evidence of acute pancreatic necrosis: 20 cases (1994-2001). JAVMA 2002;221:1724-1730.

Chan D. The inappetant hospitalized cat. Clinical approach to maximizing nutritional support. JFMS 2009: 11; 925-933.

Plumb DC. Plumb's Veterinary Drug Handbook. 6th ed. Wiley Blackwell. 2008.

Smith AN. Special concerns in cat chemotherapy. Proceedings of the ACVIM Forum 2003.

Steiner JM. Cobalamin deficiency in dogs and cats: Why should you care? Proceedings of the ACVIM Forum 2009.