Pancreatitis

The diagnosis of severe acute pancreatitis carries with it a mortality rate of up to 50% in humans [1]. Although alcohol consumption and biliary disease (the two most common causes of pancreatitis in humans) are uncommon in veterinary patients, the underlying cellular pathophysiology is likely to be similar between species, and starts with premature activation of digestive enzymes within pancreatic acinar cells. Despite extensive research into the inflammatory mediators that promulgate the systemic effects of pancreatic inflammation, advances in treatment of the disease beyond pancreatic rest and nonspecific supportive care have been minimal. Pancreatitis in veterinary patients remains predominantly a medical disease unless a specific mass (e.g., a tumor, pseudocyst, or abscess) or structural defect (i.e., biliary obstruction) can be identified.

Physiology

The exocrine pancreas produces zymogens, pancreatic secretory trypsin inhibitor (PSTI), and active enzymes (lipase, amylase, and the pro-coenzyme, procolipase). The zymogens include trypsinogen, chymotrypsinogens, kallikreinogen, proelastases, procarboxypeptidases, and prophospholipase A2. Zymogen granule secretion is the result of both neural and humoral mechanisms. Secretin and cholecystokinin (CCK) are believed to be the most important humoral mediators in stimulating zymogen secretion in dogs and cats. Trypsin is the only enzyme capable of activating itself and the other zymogens. This activation is largely controlled by the local calcium concentration. At a low calcium concentration, as is found within acinar cells, calcium binding protects the trypsinogen activation peptide from exposure. Increased calcium concentration, as is found in the pancreatic ducts and intestine, increases the sensitivity of trypsinogen to activation by trypsin. The lysosomal granules within exocrine pancreatic cells contain proteases, including cathepsin B, which can activate zymogens on contact.

Protective mechanisms that decrease the risk of premature zymogen activation include the inclusion of PSTI with zymogens, the segregation of zymogens within lipid structures, and the maintenance of high alkaline ductular flushing. Ductular PSTI protects the pancreas by binding to the active site on trypsin to prevent further zymogen activation [2]. Alkalinity is maintained by bicarbonate secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) [3]. The association of pancreatitis with CFTR mutations in humans emphasizes the importance of ductular bicarbonate secretion as a protective mechanism [3]. Duodenal brush border cells produce enterokinase, a strong protease that is responsible for zymogen activation within the intestinal lumen. This site-specific production of enterokinase helps ensure activation of zymogens within the intestinal lumen while limiting the risk of zymogen activation within the pancreas. Muscle sphincters in the pancreatic ducts help prevent reflux of enterokinase and duodenal contents into the pancreas, which is particularly important as enterokinase is not inactivated by PSTI and does not form complexes with anti-proteases.

Low levels of circulating exocrine pancreatic enzymes are commonly present in plasma and are cleared through the kidney. Circulating zymogens are bound by circulating enzyme inhibitors, α-antitrypsin and α-macroglobulin, which decrease their activity and increase monocyte-macrophage clearance, respectively.

Pathophysiology

Pancreatitis is a multifactorial process that eventually culminates in inappropriate activation of zymogens within the pancreatic parenchyma. In most patients, this is likely the result of abnormal fusion of lysosomal and zymogen granules within the acinar cells. A small subset of veterinary cases, like a large percentage of human cases, may be a result of inappropriate duodenal reflux into the pancreas [4]. The conversion of trypsinogen to trypsin starts a self-perpetuating cascade of zymogen activation with resulting auto-digestion of the pancreas and surrounding tissues. Endothelial membrane damage and increased capillary permeability lead to pancreatic edema, decreased microvascular circulation, increased free radical accumulation, and local ischemia.

As proteolytic enzymes propagate, they may overwhelm circulating anti-proteases and activate inflammatory cascades. The result may be refractory hypotensive and vasoactive shock, disseminated intravascular coagulation (DIC), multiple organ dysfunction syndrome (MODS), and death [5]. Pancreatic abscessation and pseudocysts may form in severe cases. Pancreatic pseudocysts are collections of pancreatic secretions that form secondary to fibrosis or inflammation [6]. Pancreatic abscessation may also occur and is usually sterile [7]. Both may require surgical intervention for successful outcomes.

In humans, defects in the trypsinogen, PSTI, and CFTR genes are associated with hereditary pancreatitis [2]. It is currently unknown whether there are specific hereditary causes of pancreatitis in dogs or cats, although terriers, miniature Schnauzers, and Siamese cats are over-represented.

Classification

Pancreatitis can be classified as either acute or chronic, and either form may be mild or severe. Acute pancreatitis is a completely reversible condition, despite the fact that this is often the more severe manifestation of the disease. In the cat, acute pancreatitis is further delineated as either acute necrotizing or acute suppurative disease.

Chronic pancreatitis entails irreversible histopathologic changes, including fibrosis and acinar atrophy with lymphoplasmacytic inflammation, although this form is often mild and subtle in its clinical presentation. Mild pancreatitis is associated with minimal systemic effects and low mortality. The pancreas may be edematous or show mild interstitial changes but the condition is rarely associated with necrosis of acinar cells. Severe pancreatitis is often associated with extensive pancreatic necrosis, hemorrhagic changes or suppurative inflammation, multiple organ involvement, and a poor prognosis.

Etiology and Examination Findings

Known or suspected risk factors for canine pancreatitis include breed (terriers, miniature Schnauzers), age (older than 5 years), concurrent endocrine disease (diabetes mellitus, hyperadrenocorticism, hypothyroidism, and hypertriglyceridemia), hypercalcemia, obesity, gastrointestinal disease, drugs (sulfonamides, azathioprine, L-asparaginase, estrogen, furosemide, potassium bromide, salicylates, tetracyclines, thiazide diuretics, and vinca alkaloids), toxins (cholinesterase inhibitor insecticides, cholinergic agonists, and zinc), epilepsy, infection, ischemia, and blunt abdominal trauma.8 Glucocorticoids are no longer considered a risk factor for development of pancreatitis in humans; little support exists for an association between glucocorticoids and pancreatitis in either dogs or cats. Risk factors in cats include breed (Siamese), age (older than 7 years), trauma, and concurrent disease (hepatic lipidosis or diabetes mellitus) [4,9-11]. Triaditis refers to concurrent inflammatory bowel disease (IBD), cholangiohepatitis, and pancreatitis. Feline cases may be caused by feline infectious peritonitis, toxoplasmosis, and liver or pancreatic flukes (Erythremia procyonis, Amphimerus pseudofelineus, or Opisthorchis felineus) [4,12].

Clinical signs in dogs include weakness, anorexia, vomiting, diarrhea, abdominal pain, fever, and collapse. Signs in cats include lethargy, anorexia, dehydration, and jaundice. Vomiting and diarrhea are uncommonly associated with feline pancreatitis; mild weight loss or atypical behavior may be the only clinical signs in this species. Findings on physical examination include dehydration, abdominal pain, icterus, tachycardia, tachypnea, fever or hypothermia, or the presence of an abdominal mass. In some animals, particularly cats, physical examination may be unremarkable.

Sequelae

The inappropriate activation and release of digestive enzymes have a number of systemic consequences. Direct injury to the pancreatic parenchyma results in cellular necrosis and the progression of the disease from edematous to hemorrhagic and/or necrotic pancreatitis. A variety of cascades are activated that cause systemic dissemination of the deleterious consequences of pancreatic inflammation. These include the kinin/coagulation cascades, the fibrinolytic, and the complement systems. A variety of inflammatory mediators are released that can quickly turn pancreatitis into a condition affecting multiple systems; free radicals released from neutrophils and macrophages also contribute to the adverse systemic consequences. Vascular injury leads to increased capillary permeability and activation of vasoactive amines. Effects can be significant fluid and protein loss, decreased blood flow to vital tissues, dehydration, hypovolemia, and shock. Plasma protease inhibitors are consumed; protease digestion of clotting factors may worsen shock and lead to DIC. In humans the cardiac system is particularly susceptible to the systemic signals set in motion by pancreatitis. Renal, pulmonary, and hepatic changes are the result of direct contact with digestive enzymes or secondary to altered blood flow and oxygen delivery. Hepatocellular necrosis, bile duct obstruction, pulmonary edema, acute renal failure and tubular degeneration, fibrosis, and clotting disorders are all recognized sequelae of pancreatitis in human patients.