Canine pancreatic disease: What's new in diagnosis and therapy? (Proceedings)

Pancreatic pathophysiology – Acute pancreatic necrosis (APN)

The initiating event of acute pancreatitis is the premature activation of digestive zymogens within the acinar cell. 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 (tumor necrosis factor-α, interferon-α, interferon-γ, platelet-activating factor), interleukins (IL-1, IL-2, IL-6, IL-8, IL-10), nitric oxide, and free radicals are involved in the further evolution of pancreatic acinar cell necrosis and inflammation.

New findings in canine acute pancreatitis

Canine acute pancreatitis (AP) is a common disorder which may result in death if not diagnosed in a timely fashion. This frequently encountered disease remains difficult to diagnose because the clinical signs, physical examination findings, and clinicopathologic changes are often non-specific. Therefore, knowledge of risk factors of canine AP and recognition of the clinical manifestations of this disorder are important.

The risk factors discussed in this manuscript were identified in a group of dogs in which all dogs had histopathologic confirmation of AP. The control group included dogs in which histopathologic examination excluded the possibility of AP. Clinicopathologic, radiographic, and ultrasonographic findings also pertain to dogs in which a diagnosis of AP was confirmed by histopathologic examination of the pancreas.

Risk factors for canine acute pancreatitis

Breed

Yorkshire terriers are at increased risk of developing AP, whereas miniature poodles and Labrador retrievers are at decreased risk for AP. Breed predisposition may suggest that there is a hereditary component to AP. Hereditary pancreatitis in humans can occur in association with a genetic defect of lipoprotein lipase, in individuals with hypertriglyceridemia and diabetes mellitus, or as an autosomal dominant trait, of unknown etiology, with a chronic recurrent presentation, and an early onset (usually in childhood). Further investigation is needed to determine if familial lipid metabolism disorders, or other genetic defects, predispose Yorkshire terriers to AP.

Age

The mean age of dogs with AP is 8 years. Dogs with AP may be middle to older age dogs because several of the risk factors for AP (diabetes mellitus, hyperadrenocorticism, and hypothyroidism) develop in middle to older aged dogs. Obesity, which is another risk factor for AP may also be a problem of middle-aged dogs. Additionally, the increased age of dogs with AP could be a reflection of a degenerative pancreatic or extrapancreatic process, or a result of accumulating metabolic disorders that increase the risk of AP.

Sex

Males and neutered females are at increased risk compared to intact female dogs. This finding may indicate that sex hormones or other gender specific factors are involved in the pathophysiology of AP.

Overweight body condition

Overweight and obese dogs are at an increased risk of developing AP. Increased body mass index (kg/m2) has been reported to be a risk factor and a poor prognostic indicator in humans. Increased retroperitoneal and peripancreatic fat deposition is thought to increase the risk of peripancreatic fat necrosis in humans.

Diabetes mellitus, hyperadrenocorticism, and hypothyroidism

Diabetes mellitus, hyperadrenocorticism, and hypothyroidism are all associated with increased risk for AP. It is possible that lipid metabolism disorders are responsible for the increased risk. Hypertriglyceridemia is a risk factor in humans and is seen in dogs with diabetes mellitus, hyperadrenocorticism, and hypothyroidism. Hypertriglyceridemia has been reported in association with naturally occurring canine AP.3 Experimentally induced hypertriglyceridemia initiates pancreatic injury but does not seem to be a consequence of experimentally induced pancreatitis in the dog. These findings would support a hypothesis of hypertriglyceridemia being a risk factor, rather than a consequence of canine AP. However, many other metabolic abnormalities associated with endocrinopathies could be involved.

Prior gastrointestinal disease

Prior gastrointestinal disease (colitis, gastrointestinal parasites, hiatal hernia, or inflammatory bowel disease) is a risk factor for canine AP. Chronic inflammation of the gastrointestinal tract, e.g. proximal duodenum and transverse colon, may increase local inflammation and predispose to AP.

Epilepsy

Epilepsy is a risk factor for canine AP. The reason for this association is not known, however, it may be due to anticonvulsant therapy or pancreatic ischemia during seizure activity.

Possible risk factors for canine acute pancreatitis

Thromboembolic disease

Thromboembolism was observed more commonly in dogs with AP compared to control dogs.1 However, thromboembolism may develop as a result of AP and is not necessarily a risk factor for AP. It is possible that proteolytic enzymes released from the pancreas cause endothelial damage which results in infarct and thrombus formation. On the other hand, it is conceivable that an underlying coagulopathy, such as that associated with hyperadrenocorticism, causes infarct and thrombus formation, impairs pancreatic blood flow, and results in AP.

Atherosclerosis

Atherosclerosis was more common in dogs with AP compared to control dogs.1 Hypothyroid dogs are predisposed to atherosclerosis6 however, atherosclerosis was also observed in a dog that had no evidence of hypothyroidism on post mortem examination. In humans, hypertriglyceridemia is a risk factor for pancreatitis, but its role in atherosclerosis remains controversial. Hypertriglyceridemia may be a risk factor for both AP and atherosclerosis in the dog.

Administration of trimethoprim/sulfa antibiotics

Dogs with AP receive significantly more trimethoprim/sulfa than other dogs. This finding may reflect the severity of the disease and not necessarily a risk factor. Sulfonamides have been reported as a risk factor in humans, and in some of the human patients the association was confirmed with re-challenge. Hypersensitivity reaction or toxic effects are suspected. Although trimethoprim/sulfa administration has not been reported as a risk factor for AP in dogs, other adverse reactions have been documented, and some were suspected of being immune-mediated.

Factors that may not be risk factors for canine acute pancreatitis

Steroids

Dogs with and without AP receive a variety of glucocorticoids administered at different doses and frequencies, prior to referral. However, dogs with AP do not receive significantly more glucocorticoids than other dogs. Therefore, in the wide range of inconsistent clinical use of steroids, steroid administration prior to referral does not appear to increase the risk of AP in dogs. These clinical findings agree with experimental evidence that shows that glucocorticoid administration does not cause AP in the dog.

Some clinicopathologic abnormalities associated with canine acute pancreatitis

Hypercalcemia or hypocalcemia

Hypercalcemia occurs in about 15% of dogs with AP. Hypercalcemia is a risk factor for human AP, and acute but not chronic hypercalcemia has been shown to experimentally induce AP in cats.9, 10, 11 Calcium is thought to facilitate the activation of trypsinogen, and increase the stability and activity of trypsin, thereby increasing the activation of other pancreatic digestive enzymes. Additionally, calcium is thought to cause pancreatic hypersecretion by increasing cholecystokinin release. Hypocalcemia has also been reported in dogs with AP.

Hypoglycemia or hyperglycemia

Serum glucose concentrations may vary considerably in dogs with AP. Hypoglycemia may be due to, sepsis, concurrent liver disease, differences in breed-related metabolism, or insulin treatment of diabetic dogs that have anorexia or vomiting. Hyperglycemia has been reported in dogs with spontaneous AP with and without diabetes mellitus, and in dogs with experimentally induced AP with and without permanent diabetes mellitus. In experimental dog models of concurrent diabetes mellitus and AP, dogs with both diseases had decreased glucose tolerance and prolonged hyperglycemia when compared to dogs with diabetes mellitus alone.12

Amylase and lipase activity

Serum amylase activity was increased in 69% of dogs however, serum lipase activity was increased in less than 40% of dogs with AP. Therefore, serum amylase and lipase elevations are not a consistent finding in canine AP. Since elevations in serum amylase and lipase activities are also not specific for AP it is concluded that the diagnostic value of these tests is limited.

Coagulopathies

Evidence of bleeding such as petechiation, ecchymosis, epistaxis, bruising, or a hematoma, is observed in 11% of dogs with AP. Thrombocytopenia has been documented in up to 59% of dogs with AP. Additionally, prolonged partial thromboplastin time (PTT) and prothrombin time (PT) were noted in 61% and 43% of the dogs in which they were measured, respectively. These clinical abnormalities are in agreement with evidence of thrombocytopenia and coagulopathies associated with experimental canine AP.13 In experimental canine AP, a decrease in platelets, complement, and antithrombin III was observed along with an increase in fibrinogen and plasminogen, and prolongations in PTT and PT. It is possible that complement catabolism by pancreatic proteolytic enzymes causes a consumptive coagulopathy. In human patients with spontaneous AP, increased degradation of von Willebrand's factor, as well as activation of the kallikrein-kinin system have been documented. It is possible that bleeding abnormalities contribute to the fatal outcome of some dogs with AP. Coagulation testing is therefore recommended in all dogs suspected of having AP. Prompt diagnosis and appropriate treatment of bleeding disorders may improve the prognosis of dogs with AP.

Lipemia

Gross lipemia was observed in 26% of dogs with AP, and cholesterol concentration was elevated in 48% of dogs. Lipemia and hypercholesterolemia may be the result of concurrent endocrinopathies. Obesity or overweight body condition is also associated with abnormal lipid metabolism. Lipoprotein profiles found in obese dogs are similar to those found in dogs with experimentally induced AP. Hypertriglyceridemia is a risk factor for AP in humans, and is associated with AP in dogs, however, the causality of this association is not yet defined.

Abdominal radiographic and ultrasonographic abnormalities in canine acute pancreatitis:

Abdominal ultrasonographic abnormalities are consistent with a diagnosis of AP more frequently than abdominal radiographic abnormalities. However, in some cases, abdominal ultrasonographic abnormalities are not apparent, while abdominal radiographs are suggestive of AP. Therefore, it is recommended that both imaging studies should be performed when faced with a suspected case of AP. Additionally, abdominal radiographs are a valuable diagnostic tool in any case of suspected AP because other causes of gastrointestinal disease must be ruled out. Abdominal radiographs are not suggestive of AP in 76% of dogs with histopathologic confirmation of AP. Therefore, in dogs suspected of having AP, abdominal ultrasonography should be performed even if abdominal radiographs are not suggestive of AP.

References

1. Hess R, Kass P, Shofer F, et al. Evaluation of risk factors for fatal acute pancreatitis in dogs. J Am Vet Med Assoc 1999;214 (1):46-51.

2. Hess R, Saunders H, Van-Winkle T, et al. Clinical, clinicopathologic, radiographic, and ultrasonographic abnormalities in dogs with fatal acute pancreatitis: 70 cases (1986-1995). J Am Vet Med Assoc 1998;213 (5): 665-670.

3. Whitney MS, Boon GD, Rebar AH, et al. Effects of acute pancreatitis on circulating lipids in dogs. Am J Vet Res 1987;48:1492-1497.

4. Saharia P, Margolis S, Zuidema GD, et al. Acute pancreatitis with hyperlipemia: Studies with an isolated perfused canine pancreas. Surgery 1977;82:60-67.

5. Bass VD, Hoffmann WE, Dorner JL. Normal canine lipid profiles and effects of experimentally induced pancreatitis and hepatic necrosis on lipids. Am J Vet Res 1976;37:1355-1357.

6. Barrie J, Watson TDG. Hyperlipidemia. In: Bonagura JD, ed. Kirk's current veterinary therapy XII. Small animal practice. Philadelphia: WB Saunders Co, 1995;430-434.