Diagnosing Pancreatitis in Dogs and Cats by Laboratory Methods

Laura D. West, DVM and Frederic S. Almy, DVM, MS, Diplomate ACVP

Class of 2007 (West) and Department of Pathology (Almy), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Pancreatitis is inflammation of the pancreas resulting from autodigestion by prematurely activated zymogens.¹ It is the most common disorder of the canine exocrine pancreas and is being diagnosed more frequently in cats as awareness increases and diagnostic tools improve.^1,2 The disease can be classified as acute (reversible following removal of inciting cause) or chronic (irreversible changes from on-going inflammation), and mild or moderate to severe.¹ Cats tend to have more of a chronic disease than dogs.² The diagnosis of pancreatitis is usually presumptive, as pancreatic biopsy is not always an option. Although several diagnostic tests have been advocated for use in the diagnosis of pancreatitis, many of them are not sensitive enough to be clinically useful. The primary focus of this review is to determine which diagnostic tests would be most useful in detecting pancreatitis in dogs and cats.

Etiology

The underlying cause of most cases of pancreatitis is usually unknown in both dogs and cats; however, there is a considerable list of associated risk factors. Obese animals as well as animals fed a diet high in fat are more prone to developing pancreatitis.^1,3 Hyperlipidemia has been associated with pancreatitis, although it is unclear whether it is a result of the pancreatitis or part of the cause. Certain breeds of dogs are considered predisposed to developing pancreatitis, such as the miniature schnauzer or terrier breeds.^1,3 A large number of drugs and drug classes have been thought to cause pancreatitis in people, but a direct causal relationship has not been established. Drugs used in veterinary medicine that may be associated with pancreatitis are numerous and include L-asparaginase, azathioprine, estrogen, furosemide, potassium bromide, salicylates, sulfonamides, tetracyclines, thiazide diuretics and vinca alkaloids, among others.^1,3

Additional causes or risk factors for pancreatitis include exposure to scorpion venom, zinc toxicosis, hypercalcemia, congenital anomalies of the pancreatic duct system, reflux from the duodenum into pancreatic ducts (secondary to surgical creation of a closed duodenal loop, blunt trauma, or vomiting), surgical manipulation (rare), pancreatic ischemia and endocrinopathies (hypothyroidism, diabetes mellitus, hyperadrenocorticism).^1,3

In cats, toxoplasma gondii and Amphimerus pseudofelineus (hepatic fluke) have an established causal relationship with pancreatitis. Feline infectious peritonitis and panleukopenia have also been implicated. As in the dog, blunt trauma, surgical manipulation and ischemia can result in pancreatitis. Organophosphate intoxication and inflammatory diseases of the liver and intestines are also implicated as causes.^2,3

Pathophysiology

In the normal pancreas, proteolytic and phospholipolytic enzymes are synthesized, stored and secreted as inactive zymogens and it is these enzymes that are utilized in the majority of diagnostic tests for pancreatitis. The pancreatic zymogens are only activated once they are cleaved, a process which does not normally occur until they reach the small intestine. Once in the small intestine, enteropeptidases from duodenal enterocytes cleave trypsinogen to make trypsin, which can then activate other zymogens.¹ 

Pancreatitis is the end result of a cascade of events but is ultimately caused by the autodigestion of the pancreas.⁴ Current literature suggests that this cascade of events begins with a decrease in secretion of pancreatic enzymes in response to some noxious stimulus.⁴ Subsequent to the decreased secretory activity, abnormal fusion of lysosomes and zymogen granules results in premature, intrapancreatic activation of trypsinogen.^1,4

When premature activation of trypsinogen occurs, there are mechanisms in place which limit the activation of other zymogens. First, trypsin is very effective at hydrolyzing itself. Second, pancreatic secretory trypsin inhibitor is synthesized, stored and secreted with the digestive enzymes. If significant activation of trypsin occurs within the acinar cell or duct system, this molecule will inhibit trypsin activity. Additionally, α-macroglobulin and α1-proteinase inhibitor are protease inhibitors in the plasma.¹ However, once inhibitory mechanisms are overwhelmed, more zymogens become activated, inflammatory mediators and free radicals are released, and pancreatitis develops.¹

Clinical Signs

Common clinical signs in dogs with acute pancreatitis include anorexia (91%), vomiting (90%), weakness (79%), and abdominal pain (58%).^1,5 Abdominal palpation may reveal a cranial abdominal mass.^1,3 A retrospective study of 70 cases of acute canine pancreatitis reported dehydration in 97%, icterus in 26%, fever in 32%, abdominal pain in 58%, and obesity in 43% of dogs at the time of initial examination.⁵ Other systemic complications can include respiratory distress, bleeding disorders and cardiac arrhythmias.^1,3

On the other hand, cats have extremely variable histories and clinical signs. More typical clinical signs include anorexia (97%), lethargy (100%), and dehydration (92%).⁶ Vomiting and abdominal pain, while common in the dog, are less frequently reported in the cat (35% and 25%, respectively).⁶ Other clinical signs reported include hypothermia, dyspnea, diarrhea, ataxia, and weight loss.⁶ Pancreatitis in cats has a tendency to occur with certain other diseases, such as cholangiohepatitis/cholestasis, nephritis, diabetes mellitus, and inflammation or ulceration of the intestines.^2,3

Diagnostic Laboratory Tests

Complete Blood Count (CBC) / Blood Chemistry

Abnormalities detected by standard CBC and blood chemistry analysis are not specific to canine pancreatitis and can be highly variable. A leukocytosis with a left shift is common. Toxic change may be associated with acute pancreatic necrosis. A relative polycythemia or anemia can be seen. Azotemia is a common finding and can be either pre-renal due to dehydration or due to secondary acute renal failure. Liver enzyme activities (ALT, AST, ALP) are often increased, probably due to hepatic ischemia or hepatic damage caused by toxic products from the pancreas. Additional findings include hyperbilirubinemia due to hepatocellular damage or cholestasis, hyperglycemia caused by hyperglucagonemia, stress, or damage to pancreatic islet cells, hypocalcemia associated with hypoalbuminemia or calcium deposition, hypercholesterolemia, hypertriglyceridemia, and hyperlipidemia.^1,3,5

CBC and chemistry findings in feline pancreatitis are also quite variable and nonspecific. In cats, increased liver enzyme activities can be caused by concurrent hepatic lipidosis or cholangitis/cholangiohepatitis. Hyperbilirubinemia and hyperglycemia are also commonly seen.^2,3

Amylase and lipase

The activity of serum amylase and lipase can be measured; however, these enzymes do not originate exclusively from the pancreas.⁴ The main sources of serum amylase include the pancreas, liver, and small intestine. Several forms of lipase exist (pancreatic lipase, colipase, and lipoprotein lipase) but the pancreas and gastric mucosa are the only known sources.⁷ Regardless of origin, the overall function of amylase and lipase remains the same, meaning that elevations in enzyme activity do not necessarily indicate pancreatic dysfunction .⁴ In the past, these enzymes were used to diagnose canine pancreatitis; however, amylase and lipase have recently been shown to have low sensitivity (62% and 73%,  respectively) and specificity (57% and 55%, respectively).⁴ In one study regarding the utility of amylase and lipase in the diagnosis of feline pancreatitis, no significant difference was found in the serum amylase and lipase activities between cats with acute pancreatitis, cats sick with non-pancreatic disease, and healthy control cats.⁸ Additionally, amylase and lipase can be increased in nonpancreatic diseases such as renal disease (decreased clearance) and gastrointestinal disease. In dogs, corticosteroid administration can cause significant increases in serum lipase.^3,7 Because the level of enzyme activity is not specific to the pancreas, serum amylase and lipase activities are now considered to be of very little value in the diagnosis of pancreatitis in dogs or cats.^1,2

Trypsin activation peptides (TAP)

Trypsin activation peptides (TAP) are the small peptides resulting from the cleavage of trypsinogen to give trypsin. Because trypsinogen should only be activated in the small intestine, TAP is normally absent from or minimally present in the circulating blood. Premature activation of trypsinogen, such as in pancreatitis, can lead to the presence of TAP in serum or urine.⁴ However, serum TAP is not very specific to pancreatitis as it may increase in severe renal disease.^1,7 Additionally, serum TAP may not become increased in mild pancreatitis.⁷ In contrast, urinary TAP is highly specific, but very insensitive.^1,4 To further complicate the issue, TAP is very labile in serum or urine.⁴ Taking into account the cost and limited availability of the test, along with the lack of sensitivity and the labile nature of the peptide, TAP is not considered a clinically useful test for the diagnosis of pancreatitis.¹

Trypsin α-1 proteinase inhibitor complex

As previously mentioned, plasma trypsin α-1 proteinase inhibitor is one of the mechanisms preventing inappropriate activation of trypsinogen. With experimental pancreatitis in dogs, a higher concentration of the inhibitor complex can be found in circulation. However, a significant increase was not found in dogs with spontaneous pancreatitis.⁴ Thus, assays developed to measure trypsin α-1 proteinase inhibitor complex concentration were not found to be clinically useful in the diagnosis of canine pancreatitis.^1,4

Trypsin-like immunoreactivity (TLI)

The trypsin-like immunoreactivity assay is species specific and measures trypsinogen, trypsin and some trypsin molecules bound to proteinase inhibitors. In health, only small amounts of trypsinogen and no trypsin should be present in serum.⁴ Assays for canine TLI (cTLI) and feline TLI (fTLI) are the definitive test for exocrine pancreatic insufficiency.⁹ However, current research on cTLI and fTLI in the diagnosis of pancreatitis indicates the sensitivity is low in both dogs and cats. Steiner et al. reported a sensitivity of 36.4% in the diagnosis of canine pancreatitis.¹⁰ When the recommended cut off of 100μg/L is used to diagnose pancreatitis in cats, the overall sensitivity is low (28 - 33%).^11,12 Feline TLI values are reported to be significantly higher in cats with pancreatitis (mean 100.1 ± 43.0) compared to cats sick with non-pancreatic disease (34.3 ± 4.9) and healthy cats (33.6 ±2.7) according to a study by Parent et al. However, the range of values for cats with pancreatitis (14.8 to 540μg/L) is extensive, meaning that while some cats have significantly elevated TLI values, others have values far below the 100μg/L cut-off.⁸ Overall, the data suggests that serum TLI is not useful in screening dogs or cats for pancreatitis. Although an elevated TLI can be seen with acute pancreatitis, a normal serum TLI does not rule out the presence of pancreatitis.⁹

Pancreatic lipase immunoreactivity (PLI)

While the function of pancreatic lipase is the same as any other lipase in the body, the molecular structure is unique. For this reason, a radioimmunoassay and subsequently an enzyme-linked immunosorbent assay (ELISA) were developed and validated for dogs to measure pancreatic lipase immunoreactivity (cPLI).^13,14 Steiner et al. reported a sensitivity of 81.8% for serum cPLI in the diagnosis of pancreatitis in dogs using a cut off value of 250μg/L.¹⁰ In contrast to serum lipase, cPLI concentration is not affected by decreased glomerular filtration rate or gastritis.⁴ A radioimmunoassay for feline pancreatic lipase immunoreactivity has been developed and validated.¹⁵ In a study of experimentally induced pancreatitis in cats, both serum fTLI and fPLI concentrations increased initially, but fPLI concentrations remained elevated longer.⁴ Forman et al. reported overall sensitivity of 67% and specificity of 91% for fPLI in the diagnosis of pancreatitis.¹¹ Research thus far has indicated that cPLI and fPLI assays are the most sensitive laboratory tests available for the diagnosis of pancreatitis.

Other Diagnostic Tests

Diagnostic imaging

Thoracic and Abdominal radiographs

Thoracic radiographs from patients with pancreatitis are usually normal; however, pleural effusions, edema and pneumonia have been reported in dogs and cats.^3,4,16 Abdominal radiography has a very low sensitivity for diagnosing pancreatitis. In one retrospective study, abdominal radiographic findings were consistent with a diagnosis of pancreatitis in 24% of 41 cases.⁵ Findings associated with pancreatitis are nonspecific and often absent; however, it remains a useful tool in the work-up of a vomiting dog with abdominal pain or the cat with vague signs of illness. Radiographic signs of pancreatitis include poor serosal detail in the right cranial abdomen, displacement of viscera surrounding the pancreas (stomach to the left, increased angle between pyloric antrum and proximal duodenum, descending duodenum to right, transverse colon caudally), and dilated hypomotile descending duodenum.^1,3,4,17

Abdominal ultrasound

Abdominal ultrasound is highly specific for pancreatitis as long as stringent criteria are applied.^1,11 A retrospective study of canine pancreatitis found ultrasonographic changes consistent with a diagnosis of pancreatitis in 68% of 34 cases of confirmed pancreatitis based upon histopathologic findings.5 Forman et al. reported the sensitivity in cats to be 80% for moderate to severe pancreatitis and 62% for mild pancreatitis (67% overall sensitivity).¹¹ However, other studies have reported lower sensitivities (24 - 35%).^12,16 The normal pancreas can be challenging to identify due to its small size, similar echogenicity to surrounding fat, and lack of a well-defined capsule.¹⁸ Opinions differ as to whether the normal pancreas is visible on ultrasound. A prospective study of 21 client-owned cats with signs consistent with pancreatitis and 8 apparently healthy shelter cats reported the pancreas to be visible in all 8 healthy cats.¹¹ This was in contrast to another study which reported the pancreas to only be visible ultrasonographically in cases that had pancreatic abnormalities.¹⁹ A retrospective study evaluating the use of ultrasound in diagnosing pancreatitis in cats found that the presence or absence of concurrent disease, gross or histologic distribution of pancreatitis, histologic duration, severity and location, clinical suspicion, and operator experience were not associated with ultrasonographic diagnosis of pancreatitis.¹⁶ The use of ultrasound in conjunction with other diagnostic tests can be very useful in the evaluation of pancreatitis.

Computed Tomography

In human medicine, computed tomography (CT) is the most useful imaging modality in diagnosing pancreatitis.¹ One report on the use of CT for diagnosing histologically confirmed canine pancreatitis reported a sensitivity of 64%.20 The reported sensitivity for CT in cats is low (20%).¹² Based on the expense, inconsistent availability, difficulties imaging the feline pancreas and the low sensitivity, CT does not appear to be a clinically useful test in diagnosing feline pancreatitis.

Summary of Diagnostic Testing

Although abnormalities detected on a CBC, blood chemistry profile or abdominal radiographs are typically nonspecific, they are an important part of the work up for potential pancreatitis cases. Measurement of serum amylase and lipase, trypsin activation peptides, and trypsin-like immunoreactivity are of limited use when screening for canine or feline pancreatitis, and if used, should be interpreted in light of their limitations. The most sensitive noninvasive diagnostic test for pancreatitis is the cPLI for dogs and fPLI for cats. Ultrasound is also a useful test that can aid in the diagnosis of pancreatitis. Finally, noninvasive methods for diagnosing pancreatitis require the integration of all available information.

Treatment and Prognosis

Generally, treatment in dogs and cats is supportive and directed towards restoration of blood volume with intravenous fluids ± colloidal fluids or plasma, controlling vomiting, providing analgesia, and addressing any suspected inciting cause.^1,9 Central acting antiemetics are the treatment of choice for vomiting.⁹ Analgesia is an important component to therapy, even in patients which do not present with obvious abdominal pain.^1,9  Because pancreatitis rarely has infectious components, antibiotics are usually not indicated.¹ Corticosteroid therapy should only be used in cases where the cause is suspected to be autoimmune or in cats with concurrent diseases that warrant corticosteroid treatment (inflammatory bowel disease (IBD), cholangiohepatitis).^1,2,9 Oral intake should be restricted in cases of incessant vomiting for only a short period of time.¹ If a cat is unable to take in oral food or water for more than 2-3 days, other routes of nutrition should be considered to prevent development of hepatic lipidosis and malnutrition.⁹ For dogs or cats, though, enteral nutrition is preferred over parenteral.¹

The prognosis in canine pancreatitis is quite variable and difficult to predict.¹ Some dogs present with an acute fulminating pancreatitis and die regardless of supportive measures. Others can fully recover following an isolated severe event. Chronic or recurrent cases may persist until an acute exacerbation results in death or the animal is euthanized due to poor quality of life and expense of treatment.¹ The prognosis in feline pancreatitis is directly related to the severity of the disease, extent of necrosis, occurrence of systemic or pancreatic complications, duration of disease and presence of concurrent disease.² Additionally, an ionized calcium below 1.00 mmol/L is associated with a 77% mortality rate.²

References

1. Williams DA, Steiner JM. Canine Exocrine Pancreatic Disease. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, Diseases of the Dog and Cat, 6th ed. St. Louis, Elsevier Saunders, 2005, pp. 1482-1487.

2. Steiner JM, Williams DA. Feline Exocrine Pancreatic Disease. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, Diseases of the Dog and Cat, 6th ed. St. Louis, Elsevier Saunders, 2005, pp. 1489- 1491.

3. Simpson, KW. Diseases of the Pancreas. In Tams T. (ed): Handbook of Small Animal Gastroenterology, 2nd ed. St. Louis, W. B. Saunders Co, 2003, pp. 353-365.

4. Steiner JM. Diagnosis of acute pancreatitis. Vet Clin North Am Small Anim Pract 2003; 33: 1181-1195.

5. Hess RS, Saunders HM, Van Winkle TJ, et al. Clinical, clinicopathologic, radiographic, and ultrasonographic abnormalities in dogs with acute pancreatitis: 70 cases (1986-1995). J Am Vet Med Assoc 1998 Sep1; 213(5): 665-70.

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

7. Bounous, DI. Digestive System. In Latimer KS, Mahaffey EA, Prasse KW (eds): Clinical Pathology, 4th ed. Ames, Iowa, Iowa State Press, 2003, pp. 215-219.

8. Parent CR, Washabau J, Williams DA, et al. Serum trypsin-like immunoreactivity, amylase and lipase in the diagnosis of feline acute pancreatitis. J Vet Intern Med 1995; 9: 194 (abstract).

9. Zoran DL. Pancreatitis in Cats: Diagnosis and Management of a Challenging Disease. J Am Anim Hosp Assoc 2006; 42:1-9.

10. Steiner JM, Broussard J, Mansfield CS, et al. Serum canine pancreatic lipase immunoreactivity (cPLI) concentrations in dogs with spontaneous pancreatitis. J Vet Intern Med 2001; 15:274 (abstract).

11. Forman MA, Marks SL, De Cock HEV, et al. Evaluation of Serum Feline Pancreatic Lipase Immunoreactivity and Helical Computed Tomography versus Conventional Testing for the Diagnosis of Feline Pancreatitis. J Vet Intern Med 2004;18:807-815

12. Gerhardt A, Steiner JM, Williams DA, et al. Comparison of the sensitivity of different diagnostic tests for pancreatitis in cats. J Vet Intern Med 2001;15:329-333.

13. Steiner JM, Williams DA. Development and validation of a radioimmunoassay for the measurement of canine pancreatic lipase immunoreactivity (cPLI) in serum. J Vet Intern Med 2000;14:378 (abstract).

14. Steiner JM, Teague SR, Williams DA. Development and analytic validation of an enzyme-linked immunosorbent assay for the measurement of canine pancreatic lipase immunoreactivity in serum. Can J Vet Res 2003;67:175-182.

15. Steiner JM, Wilson BG, and Williams DA. Development and analytic validation of a radioimmunoassay for the measurement of feline pancreatic lipase immunoreactivity in serum. Can J Vet Res 2004;68:309-314.

16. Saunders HM, Van Winkle TJ, Drobatz K, et al. Ultrasonographic findings in cats with clinical, gross pathologic, and histologic evidence of acute pancreatic necrosis: 20 cases (1994-2001). J Am Vet Med Assoc 2002;221:1724-1730.

17. Steiner JM, Broussard J, Mansfield CS, et al. Serum canine pancreatic lipase immunoreactivity concentrations in dogs with spontaneous pancreatitis. J Vet Intern Med 2001;15:274 (abstract).

18. Mahaffey MB, Barber DL. The peritoneal space. In Thrall DE (ed): Textbook of veterinary diagnostic radiology, 4th ed. Philadelphia, Elsevier Saunders, 2002, pp. 516-539.

19. Swift NC, Marks SL, MacLachlan NJ, Norris CR. Evaluation of serum feline trypsin-like immunoreactivity for the diagnosis of pancreatitis in cats. J Am Vet Med Assoc 2000;217: 37-42.

20. SpillmanT, Litzlbauer H, Moritz A, et al. Computed tomography and laparoscopy for the diagnosis of pancreatic diseases in dogs. Proceedings of the 18th ACVIM forum. Seattle, WA, 2000:485-487 (abstract).

Acknowledgement

"Ying Yang" is from the Art Gallery section of the PETIQUE NY website and is used with permission.

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