Is it pancreatitis?

Pancreatitis, an inflammatory condition of the pancreas, occurs frequently in dogs and cats.1-3 We do not know the prevalence of pancreatitis in dogs and cats, but recent studies suggest that it is underdiagnosed.1,2

A recent study of dogs presented for necropsy to the Department of Pathology at the Animal Medical Center in New York, N.Y., showed that 64% of 73 dogs that died or were euthanized for various reasons had evidence of an inflammatory infiltrate of the pancreas.2 Although these findings were surprising, this study did not investigate which of these patients had lesions that were clinically significant.2

In a large retrospective study of necropsy findings, 1.5% of 9,342 canine and 1.3% of 6,504 feline pancreata showed important pathologic lesions.1 Also, according to this study, 59% and 46% of all canine and feline patients with exocrine pancreatic lesions, respectively, had evidence of pancreatitis.1

Dogs and cats with pancreatitis commonly display nonspecific clinical signs, so the condition can be difficult to diagnose. But there also has been a lack of diagnostic tests for pancreatitis that are both sensitive and specific. In this article, I provide an overview of the available diagnostic tests, including a new serum test. A summary of the utility of the diagnostic tests for pancreatitis is shown in Table 1.

Table 1 : Utility of Various Diagnostic Tests for Pancreatitis in Dogs and Cats

CLASSIFICATION

Pancreatitis can be classified based on clinical, etiologic, and histopathologic features.4 In the veterinary literature, pancreatitis has been classified based on various parameters, such as histopathologic changes and clinical presentation.5-8 Unfortunately, a universally accepted multidisciplinary classification has not been proposed or agreed on in veterinary medicine. In contrast, several international multidisciplinary symposia have been held to establish a classification system for pancreatitis in people, and the use of this classification system has been universally agreed on in human pancreatology.4 Since this system is based on simple clinical and histopathologic features that are also observed in dogs and cats, I use the human classification system for pancreatitis in dogs and cats.4

According to this classification system, pancreatitis can be acute or chronic. Acute pancreatitis is an inflammatory condition of the pancreas that, after removal of the inciting cause, is completely reversible.4 In contrast, chronic pancreatitis is characterized by irreversible changes of the exocrine pancreas, such as atrophy or fibrosis.4 Both forms of pancreatitis can be mild or severe. Mild forms of pancreatitis are associated with little or no pancreatic necrosis or systemic effects, and affected patients often recover. In contrast, severe forms of pancreatitis are associated with extensive pancreatic necrosis, multiple organ involvement, and often a poor prognosis.

CLINICAL PICTURE

The clinical signs in dogs and cats with pancreatitis depend on the severity of the disease. Mild cases may remain subclinical, while more severe cases may present with a wide variety of clinical signs.

In a recent retrospective study of 70 dogs with fatal pancreatitis, clinical signs reported included anorexia in 91% of the cases, vomiting in 90%, weakness in 79%, abdominal pain in 58%, dehydration in 46%, and diarrhea in 33%.7 These findings are somewhat surprising as abdominal pain is the key clinical sign of pancreatitis in people. Thus, the question arises as to whether dogs with pancreatitis have abdominal pain less frequently than people do or, as I think is more likely, whether we fail to correctly identify abdominal pain. Keep in mind that retrospective studies could underestimate the true prevalence of abdominal pain because of lack of reporting, a difference in investigators, or other factors. Classically, diarrhea has not been described as a typical clinical sign of pancreatitis. However, 33% of dogs with fatal pancreatitis in this study had diarrhea, so it seems prudent to evaluate dogs that have diarrhea for pancreatitis.

Cats, even those with severe pancreatitis, present with less specific clinical signs than do dogs. In a recent review of 159 cats with pancreatitis, clinical signs reported included anorexia in 87%, lethargy in 81%, dehydration in 54%, weight loss in 47%, vomiting and hypothermia in 46%, icterus in 37%, fever in 25%, abdominal pain in 19%, diarrhea in 12%, and a palpable abdominal mass in 11%.9 Especially remarkable in this report is the low incidence of vomiting and abdominal pain in cats with pancreatitis.

Clinical signs in patients with pancreatitis are due either to prematurely activated pancreatic enzymes or to systemic effects of the inflammatory response to pancreatic autodigestion. Recent experimental data in rats and mice suggest that the exocrine pancreas responds to many different noxious stimuli in a similar fashion.10 The first common change reported is decreased pancreatic enzyme secretion.10 This change is followed by the formation of giant cytoplasmic vacuoles in acinar cells, visible only by electron microscopy.10 Biochemical studies have shown that these vacuoles are the product of co-localization of zymogens of digestive enzymes and lysosomal enzymes, which are normally strictly segregated.10 The ensuing decrease in pH in the giant cytoplasmic vacuoles, the presence of the lysosomal enzymes such as cathepsin B, or both lead to premature trypsinogen activation. Trypsin in turn activates other zymogens, leading to local effects such as inflammation, pancreatic edema and hemorrhage, pancreatic necrosis, and parapancreatic fat necrosis. These local effects are associated with clinical signs such as vomiting and abdominal pain.

Until recently it was thought that systemic signs seen in patients with pancreatitis, like local effects, are a direct result of circulating pancreatic enzymes. While there is little doubt that some of these systemic effects, such as systemic lipodystrophy, are caused by circulating pancreatic enzymes, recent data suggest that other systemic sequelae are a consequence of the release of inflammatory mediators in response to pancreatic inflammation.11 Systemic effects seen in patients with severe pancreatitis include fever, systemic vasodilation leading to hypotension and sometimes acute renal failure, pulmonary edema leading to respiratory failure, disseminated intravascular coagulation, and in some cases multiorgan failure. A few patients also develop systemic lipodystrophy. Neurologic signs such as disorientation have been seen in people, dogs, and cats with severe pancreatitis and are sometimes referred to as pancreatic encephalopathy.

While clinical signs are not specific for pancreatitis, vomiting, anorexia, and cranial abdominal pain are key clinical signs in dogs with pancreatitis. Cats display these key clinical signs less frequently, making it more difficult for veterinary clinicians to suspect pancreatitis.

GENERAL CLINICAL PATHOLOGY

Complete blood count and serum chemistry profile results often show mild and nonspecific changes in both dogs and cats with pancreatitis.6,7 In a study of 70 dogs with fatal acute pancreatitis, complete blood count abnormalities included a neutrophilia with a left shift in 55% of the cases, thrombocytopenia in 59%, and anemia in 29%.7 Similarly, complete blood count abnormalities in 40 cats with severe pancreatitis included anemia in 26% of the cases, hemoconcentration in 13%, leukocytosis in 30%, and leukopenia in 15%.6 While these findings may help in the overall assessment of a patient's health status, they are not useful for arriving at a specific diagnosis of pancreatitis in either dogs or cats.

Serum chemistry profiles in dogs or cats with pancreatitis may show mild elevations of hepatic enzymes.6,7 Electrolyte abnormalities are common in severe cases and may be due to dehydration or severe vomiting. Azotemia can be seen and may be due to dehydration or acute renal failure.6,7 Hypoalbuminemia may also occur. Hypocalcemia can be seen in severe cases and may be present because of hypoalbuminemia or the formation of calcium salts with fatty acids secondary to fat necrosis. In one study, a decreased plasma ionized calcium concentration was common in cats with acute pancreatitis and was significantly lower in cats with fatal disease.12 However, there was great overlap between the groups,12 and the plasma ionized calcium concentration lacked sensitivity for identifying fatal disease.

Urinalysis often reveals an elevated urine specific gravity secondary to dehydration. However, in severe cases acute renal failure may ensue; consequently, the urine specific gravity may drop and casts may be seen in the sediment.

Thus, none of the complete blood count, serum chemistry profile, or urinalysis findings are specific for pancreatitis. However, these parameters can help you narrow your list of differential diagnoses for such nonspecific clinical signs as vomiting, anorexia, and lethargy. Also, general clinical pathology results will help you assess a patient's overall health status and may help you determine how aggressively to pursue further workup and management.

DIAGNOSTIC IMAGING

Radiography

Abdominal radiography is nonspecific for canine or feline pancreatitis. Abdominal radiographs may reveal decreased contrast in the cranial abdomen and displacement of abdominal organs in affected patients. These changes are rather subjective; however, abdominal radiographs are crucial in ruling out other causes of acute-onset vomiting and anorexia, such as an obstruction due to a foreign body.

Ultrasonography

Abdominal ultrasonography was first described as a diagnostic tool for pancreatitis in veterinary patients in the mid-1980s. Since then, both the technology and expertise of veterinary radiologists in this area have markedly increased. While this development has increased the sensitivity of this diagnostic modality for pancreatitis, it has decreased its specificity. The sensitivity of abdominal ultrasonography for pancreatitis when performed by a veterinary radiologist has been reported to be up to 68% in dogs and up to 35% in cats.7,13

Ultrasonographic findings in dogs and cats with pancreatitis include pancreatic enlargement, changes in the echogenicity of the pancreas (hypoechogenicity is thought to indicate pancreatic necrosis and hyperechogenicity pancreatic fibrosis) and peripancreatic fat (hyperechogenicity is thought to indicate peripancreatic fat necrosis), fluid accumulation around the pancreas, a mass effect in the area of the pancreas, a dilated pancreatic duct, and a swollen major duodenal papilla. When stringent criteria are applied, abdominal ultrasonography is useful in identifying pancreatitis in dogs and cats.

Computed tomography

Abdominal computed tomography is routinely used in people suspected of having pancreatitis. But it appears to lack sensitivity for diagnosing pancreatitis in cats, and data in dogs are extremely limited.8,14

MINIMALLY INVASIVE DIAGNOSTIC TESTS

Many minimally invasive diagnostic tests for canine and feline pancreatitis have been described, but few have been found to be clinically useful. However, one new test, pancreatic lipase immunoreactivity, has shown promise.

Serum lipase activity

Serum lipase activity has been used to diagnose human and canine pancreatitis for several decades.15-17 However, it has long been recognized that serum lipase activity has low sensitivity and specificity for identifying pancreatitis in either species.

Serum lipase activity has been reported to decrease in dogs after pancreatectomy, indicating that some of the serum lipase activity originates from the exocrine pancreas.18 But considerable serum lipase activity is still present in these dogs after pancreatectomy, indicating that lipase activity must originate from additional sources.18 Many cell types synthesize and secrete lipases. Any time an apolar lipid, such as a triglyceride, needs to permeate the phospholipid bilayer of a cellular membrane, a lipase is needed. These lipases of different cellular origins share a common function, so they cannot be differentiated by using a catalytic assay such as those being used to determine lipase activity in serum.

To further illustrate this phenomenon, serum lipase activity was measured in 25 dogs with exocrine pancreatic insufficiency.19 These dogs had no apparent pancreatic functional reserve, yet in these 25 dogs the mean serum lipase activity did not differ significantly from that in 74 healthy dogs, and only one dog with exocrine pancreatic insufficiency had a serum lipase activity below the lower limit of the reference range.19

In addition, many nonpancreatic conditions are associated with a marked increase in serum lipase activity, leading to an incorrect diagnosis of pancreatitis. For example, patients with conditions such as renal failure, glomerulosclerosis, glomerulonephritis, hepatic necrosis, hepatic fatty degeneration, hepatocellular carcinoma, bile duct carcinoma, lymphosarcoma, hemangiosarcoma of the heart, adenocarcinoma of the small intestine, sepsis, and amyloidosis of multiple organs have all been described as having an increased serum lipase activity.17,20 Also, heat stress and prednisone or dexamethasone administration can cause increased serum lipase activity in dogs.21-23 While some dogs with pancreatitis have elevated serum lipase activity, others have no or only mild elevations of serum lipase activity.17

Thus, serum lipase activity is neither sensitive nor specific for diagnosing pancreatitis in dogs and should only be used if an in-house assay with immediate turn-around is available and the results can be confirmed by another, more specific diagnostic modality. Finally, if serum lipase activity is analyzed, I think the results should be interpreted cautiously, and only elevations of three to five times the upper limit of the reference range should be considered suggestive of pancreatitis.

Six cats with experimentally induced pancreatitis had significantly increased serum lipase activities, but 12 cats with spontaneous pancreatitis did not.24,25 In one study, not a single cat with spontaneous pancreatitis had a serum lipase activity above the upper limit of the reference range.24 These data suggest that serum lipase activity is of no clinical usefulness in diagnosing pancreatitis in cats.24

Serum amylase activity

The diagnostic utility of serum amylase activity for canine and feline pancreatitis is similar to that of serum lipase activity. Dogs with experimentally induced pancreatitis had elevated serum amylase activities.15,16 Also, some dogs with spontaneous pancreatitis have an elevated serum amylase activity, but others have normal serum amylase activities.17 Furthermore, dogs with nonpancreatic conditions can have elevated serum amylase activities.17,20 In contrast to its effect on serum lipase activity, prednisone or dexamethasone administration in clinically healthy dogs led to a decrease in serum amylase activity.22,23 These data suggest that, as for serum lipase activity, serum amylase activity should only be used to diagnose pancreatitis in dogs if an in-house assay is available and results are available before more specific diagnostic test results can be obtained. Also, the diagnosis must then be confirmed by more accurate diagnostic modalities.

In contrast to serum amylase activity in dogs, serum amylase activity has been shown to be unchanged or decreased in cats with experimental pancreatitis.25 In another study, serum amylase activity was not significantly different among cats with spontaneous pancreatitis, clinically healthy cats, and cats with nonpancreatic diseases.24 These findings suggest that serum amylase activity has no clinical usefulness in diagnosing pancreatitis in cats.

Serum trypsin-like immunoreactivity

The serum trypsin-like immunoreactivity (TLI) assay mainly measures trypsinogen in serum but also detects trypsin and some trypsin molecules bound to proteinase inhibitors. The TLI assay is species-specific, and different assays for people, dogs, and cats have been developed and validated. In healthy patients, a small amount of trypsinogen is secreted into the vascular space, but little or no trypsin is present in serum. Serum TLI originates from the exocrine pancreas almost exclusively.18,19 Similar studies are not available in cats, but as in dogs, no evidence is available that suggests that serum TLI originates from cells other than pancreatic acinar cells.

Dogs and cats with experimental pancreatitis and some dogs and cats with spontaneous pancreatitis have increased serum TLI concentrations. 26,27 However, only 30% to 60% of dogs and cats with spontaneous pancreatitis have elevated serum TLI concentrations. This is most likely due to the short half-life of serum TLI concentration.

Trypsinogen activation peptide

When trypsinogen is activated to trypsin, a small peptide, trypsinogen activation peptide (TAP), is split from the trypsinogen molecule. Under normal conditions, trypsinogen activation occurs exclusively in the small intestine. Thus, normal dogs and cats have no or only minimal concentrations of TAP circulating in the bloodstream.28 In patients with pancreatitis, trypsinogen is activated prematurely in pancreatic acinar cells, and TAP is released into the vascular space.

However, in a clinical trial, the sensitivities of the urinary TAP-to-creatinine ratio and plasma TAP concentration for pancreatitis in dogs were suboptimal.26 The urinary TAP-to-creatinine ratio was highly specific for pancreatitis (specificity 100%) but was not sensitive, identifying only 26% of all dogs with pancreatitis.26

A recent study also evaluated serum and urinary TAP concentrations for diagnosing feline pancreatitis.29 While the urinary TAP concentration and urinary TAP-to-creatinine ratio were not significantly different in cats with pancreatitis compared with clinically healthy cats, the serum TAP concentration was significantly increased in cats with pancreatitis.29 However, the serum TAP concentration did not appear to have any advantages over the determination of serum TLI concentration.29 Also, TAP is relatively labile in plasma and urine samples, and the assay is not widely available. Thus, the use of this assay for diagnosing pancreatitis in dogs and cats cannot be recommended.

Pancreatic lipase immunoreactivity

Recently, pancreatic lipase immunoreactivity (PLI) assays have been developed and validated for dogs and cats (cPLI and fPLI, respectively).30,31 As mentioned previously, many different cell types in the body synthesize and secrete lipases. In contrast to catalytic assays for measuring lipase activity, immunoassays allow the specific measurement of lipase originating from the exocrine pancreas.

Serum cPLI concentration was measured in 25 dogs with exocrine pancreatic insufficiency, and the median serum cPLI concentration was significantly decreased compared with clinically healthy dogs.19 In addition, the serum cPLI concentration was undetectable in most (80%) of the dogs, indicating that the serum cPLI concentration mostly, if not exclusively, originates from the exocrine pancreas.19

In another study, serum cPLI concentrations were evaluated in 16 dogs with experimentally induced chronic renal failure.32 While serum cPLI concentrations were significantly higher in dogs with experimentally induced chronic renal failure than in clinically healthy dogs, 14 dogs had serum cPLI concentrations within the reference range, and none of the dogs had serum cPLI concentrations that were above the currently recommended cut-off value for pancreatitis.32

These data suggest that the serum cPLI concentration can be used as a diagnostic test for pancreatitis even in dogs with renal failure.32 Also, long-term oral administration of prednisone (2.2 mg/kg once a day for four weeks) in six healthy dogs did not affect the serum cPLI concentration.33 Finally, the sensitivity of different minimally invasive diagnostic tests was compared in 11 dogs with pancreatitis.27 The sensitivity of the serum TLI concentration was below 35% and that of serum lipase activity was less than 55%. In contrast, the sensitivity of the serum cPLI concentration for pancreatitis was above 80%.27

Recent studies in cats have shown similar results. In six cats with experimentally induced pancreatitis, both serum fTLI and fPLI concentrations did increase initially, but the serum fPLI concentration stayed elevated much longer than did the serum fTLI concentration, suggesting that, as in dogs, the serum PLI concentration is more sensitive for pancreatitis than is the serum TLI concentration.34 In another study in cats with spontaneous pancreatitis, the serum fPLI concentration was more sensitive and more specific than was the serum fTLI concentration or abdominal ultrasonography.8

While the serum PLI concentration does not allow differentiation of acute vs. chronic pancreatitis, it can be used to monitor the progress of disease (see the article "Serial serum pancreatic lipase immunoreactivity concentrations in a dog with histologically confirmed pancreatitis" in this issue).

These initial data suggest that the serum PLI concentration is highly sensitive and specific for diagnosing pancreatitis in dogs and cats. Further studies and long-term clinical experience with these new tests are required to confirm these findings. A commercial assay for measuring cPLI concentration (Spec cPL—Idexx Laboratories) has recently been released and is expected to increase the availability of cPLI measurement for veterinary practitioners. In contrast, the fPLI assay is only available through the Gastrointestinal Laboratory at Texas A&M University's Department of Small Animal Clinical Sciences (www.cvm.tamu.edu/gilab).

PANCREATIC BIOPSY

Traditionally, a pancreatic biopsy has been viewed as the most definitive diagnostic tool for pancreatitis. The presence of pancreatitis can sometimes be easily determined by the gross appearance of the pancreas. However, the absence of pancreatitis can be difficult to prove. In a recent study, histopathologic findings in dogs with pancreatitis were highly localized, suggesting that even if multiple biopsy samples are being collected, pancreatic inflammation, especially in cases of chronic pancreatitis, may be easily missed.2 And although a pancreatic biopsy itself is not associated with many complications, many patients with pancreatitis are poor anesthetic risks. In some patients, a pancreatic biopsy may help differentiate pancreatitis and exocrine pancreatic neoplasia.

Editors' note: Dr. Steiner is a paid consultant for Idexx Laboratories and is director of the Gastrointestinal Laboratory at Texas A&M University College of Veterinary Medicine.

Jörg M. Steiner, med.vet., Dr.med.vet., PhD, DACVIM, DECVIM-CA

Department of Small Animal Clinical Sciences

College of Veterinary Medicine and Biomedical Sciences

Texas A&M University

College Station, TX 77843

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