Exocrine Pancreatic Disease - Proceedings - Library - VIN

http://www.vin.com/Members/Proceedings/Proceedings.plx?C...

Front Page : Library : WVC 2004 : Small Animal : Gastroenterology : Exocrine Pancreatic Disease Back to Gastroenterology Back to Table of Contents

Feline Exocrine Pancreatic Disease (VET-192)

WESTERN VETERINARY CONFERENCE 2004
Robert J. Washabau, VMD, PhD, DACVIM School of Veterinary Medicine, University of Pennsylvania Philadelphia, PA, USA

HISTOLOGIC CLASSIFICATION

OF

FELINE PANCREATIC LESIONS

Based on a recent retrospective review of our pathology database, we have developed a revised classification scheme for feline exocrine pancreatic pathology, which is characterized in the following way: Acute necrotizing pancreatitis--Peri-pancreatic fat necrosis and/or pancreatic acinar cell necrosis (>50% of the pathology), inflammation, hemorrhage, mineralization, fibrosis. Inflammation can be present, but necrosis must be the predominant feature. Acute suppurative pancreatitis--Neutrophilic (>50%) pancreatic inflammation necrosis. Necrosis can be present, but PMN's must be the predominant feature. Chronic non-suppurative pancreatitis--Lymphocytic/plasmacytic inflammation, fibrosis, acinar atrophy. Necrosis and suppuration can be present in small amounts, but lymphocytes must be the predominant feature. Pancreatic nodular hyperplasia --Nodules of pancreatic acinar and/or ductular tissue are present. Fibrosis is not a feature of this condition. Pancreatic neoplasia--Malignancy of pancreatic origin, whether accompanied by necrosis, inflammation, fibrosis, hemorrhage, or mineralization. Pancreatic pseudocyst/abscess--Cystic structure observed at ultrasound and/or surgery and/or necropsy. Cystic cavity contains fluid, pancreatic cells, enzyme. Pancreatic atrophy--Hypoplasia, degeneration, involution, or apoptosis of the exocrine portion of the gland. The endocrine portion of the gland may be spared or involved in the same process.

FELINE ACUTE NECROTIZING PANCREATITIS

Introduction--Peripancreatic fat necrosis and acinar cell necrosis are now recognized as an important cause of morbidity and mortality in the domestic cat. Reports of this condition were uncommon prior to the early 1990's, probably related to difficulties in diagnosis as well as low incidence of disease. Some of the difficulties in the diagnosis and treatment of this disorder may have, in fact, related to preconceived notions about the same disorder in the dog. Like many other companion animal disorders, there are important differences in the natural history of the disease between cats and dogs. History--Siamese cats were reported to be at increased risk for the disease in the first retrospective study of feline pancreatitis. A more recent study suggests that most cases of pancreatitis are seen in the Domestic Short Hair breed. Lethargy (100%) and partial to complete anorexia (97%) are the most frequently reported clinical signs in cats with acute pancreatitis, but, of course, these clinical signs are not pathognomonic for pancreatitis. Lethargy and anorexia are the most important clinical signs in many feline diseases. Gastroenterologic signs are sporadic and less frequently reported. For example, vomiting (35%) and diarrhea (15%) were less frequently reported clinical signs in a retrospective study of 40 cases of feline acute pancreatitis. Similar findings were reported in a more recent study of feline pancreatitis. In canine acute pancreatitis, vomiting (90%) and diarrhea (33%) appear to be more important clinical signs. Physical Examination Findings--Physical examination findings in cats with acute pancreatitis include dehydration (92%), tachypnea (74%), hypothermia (68%), icterus (64%), tachycardia (48%), abdominal pain (25%), abdominal mass (23%), dyspnea (20%), ataxia (15%), and fever (7%). These findings clearly suggest that a "textbook" description of acute pancreatitis (e.g., vomiting, diarrhea, abdominal pain, and fever) is uncommonly seen in the domestic cat. Many of these physical examination findings are more commonly reported in canine acute pancreatitis. For example, abdominal pain (58% in dogs; 25% in cats) and fever (32% in dogs; 7% in cats) are more commonly reported in dogs with acute pancreatitis. Laboratory Findings--In 40 cats with spontaneous acute pancreatitis, laboratory abnormalities included: normocytic, normochromic regenerative anemia (55%), leukocytosis (30%), leukopenia (15%), hyperglycemia (64%), azotemia (57%), hypocalcemia (45%), hypokalemia (56%), hypoalbuminemia (24%), hyperbilirubinemia (64%), hypercholesterolemia (64%), and elevations in serum alanine aminotransferase (68%) and alkaline phosphatase (50%) activities. Similar changes were reported in a more recent retrospective review of feline acute pancreatitis. Thus, changes in red and white blood cell counts, serum activities of liver enzymes, and serum concentrations of bilirubin, glucose, and cholesterol are fairly consistent findings in spontaneous feline acute pancreatitis, just as they are in the canine disorder. Important differences between cats and dogs appear to be reflected in white blood cell counts and serum calcium concentrations. Leukocytosis is a more important clinical finding in the dog (62% in dogs; 30% in cats). Leukopenia is sometimes seen instead of leukocytosis in cats, and a worse prognosis has been attributed to leukopenia in the cat. Hypocalcemia also appears to be a more frequent finding in cats (3-5 % in dogs; 45-50% in cats. Hypocalcemia (total and serum ionized) may result from several mechanisms, e.g., acid-base disturbances, peripancreatic fat saponification, and/or parathormone resistance. Regardless of the mechanism, hypocalcemia appears to confer a worse clinical prognosis in cats-greater morbidity and mortality were reported in association with hypocalcemia in a recent retrospective report of feline acute pancreatitis. This finding suggests that cats should be monitored fairly closely for the development of hypocalcemia. Serum trypsinogen-like immunoreactivity (TLI) concentrations appear to be elevated early in feline acute pancreatitis, but some peaks may be missed during the clinical evolution of the disease. Serum amylase and lipase activities do not appear to be useful in the diagnosis of feline acute pancreatitis, whereas these enzyme activities may still have some clinical utility in the diagnosis of canine acute pancreatitis. Assays of the trypsinogen activation peptide (asp-asp-asp-asp-lys) appeared to have some promise based on experimental studies, but more recent studies have not shown consistent clinical results. Feline pancreatic-specific lipase assays (fPLI) may hold some additional benefit over feline TLI (fTLI). Indeed, fPLI may be more sensitive and specific than fTLI. Imaging Findings--The radiographic findings of acute pancreatitis in the domestic cat have not been very well characterized. It has been suggested that the radiographic findings of acute pancreatitis in the dog (e.g., increased density in the right cranial abdominal quadrant, left gastric displacement, right duodenal displacement, and gas-filled duodenum/colon) are similar in the cat. This statement has not been very well substantiated. Indeed, in several recent reports, many of these radiographic findings were not reported in cats with documented acute pancreatic necrosis. In spontaneous clinical cases, hepatomegaly and abdominal effusion are the most common radiographic findings. Hypoechoic pancreas, hyperechogenicity of the peripancreatic mesentery, and peritoneal effusion have been observed with abdominal ultrasonography in many cats with spontaneous acute pancreatitis. The sensitivity and specificity of this imaging modality have not yet been determined. Recent studies suggest a high sensitivity (>85%) but a low sensitivity (<35%). Etiology--The etiology of this disorder is incompletely understood. Biliary tract disease (e.g., cholangiohepatitis), hypercalcemic disorders, organophosphate poisoning, ischemia, trauma, idiosyncratic drug reactions (e.g., glucocorticoids), infection (Eurytrema procyonis flukes, feline infectious peritonitis, Toxoplasmosis), and lipodystrophy have been suggested as potential causes of acute pancreatitis in the cat. However, good evidence exists only for biliary tract disease, organophosphate poisoning, ischemia, trauma, infection, and lipodystrophy. Pathology in the distal common bile duct (e.g., infection, calculus, etc.) could predispose to acute pancreatitis because of the functional relationship between the major pancreatic duct and common bile duct sphincters in the cat. Indeed, perfusion of the major pancreatic duct with bile salts produces marked structural changes in the pancreatic duct and pancreas. Hypercalcemia has been suggested as a cause of acute pancreatitis in cats because of the relationship established in humans, and because of an association recently reported in dogs. Acute experimental hypercalcemia does indeed cause acute pancreatic necrosis and pancreatitis in cats, but it is probably not very clinically relevant. Chronic hypercalcemia, a more clinically relevant condition, is not associated with any changes in pancreatic morphology. Glucocorticoid administration has also been suggested as a cause of acute pancreatitis (especially in the dog), but the evidence for causality is not very substantial. Organophosphate poisoning is a potential cause of acute pancreatitis in the cat, but clinical reports suggest that it may not an important cause of acute pancreatitis in cats. Alterations in pancreatic blood flow and/or microvascular permeability may be more important mechanisms in the pathogenesis of acute pancreatitis in cats. Acute edematous pancreatitis (a mild, frequently asymptomatic form of the disease) is readily converted to an acute hemorrhagic pancreatitis through increases in microvascular permeability induced by 16,16 - dimethyl prostaglandin E2 administration in cats. Trauma, infection (e.g., flukes, FIP, Toxoplasmosis) and lipodystrophy have all been cited as occasional causes of acute pancreatitis in cats. As with the dog, it is likely that other unrecognized causes of acute pancreatitis also exist in the cat. More recent studies suggest that pre-existing inflammatory bowel disease may be an important risk factor for the development of pancreatitis (and cholangiohepatitis) in cats. There are several reasons, or contributing factors, for this association: (1) High incidence of feline inflammatory bowel disease-IBD is a common disorder in the domestic cat. In some veterinary hospitals and specialty referral centers, IBD is the most common gastrointestinal disorder in cats. (2) Clinical symptomatology-Vomiting is the most important clinical sign in cats affected with IBD. Chronic vomiting predisposes cats to raised intra-duodenal pressure and pancreaticobiliary reflux. (3) Pancreaticobiliary anatomy-Unlike the dog, the sphincter of Oddi is a common (physiological and anatomic) channel at the duodenal papilla. Thus, reflux of duodenal contents perfuses both pancreatic and biliary systems. (4) Intestinal Microflora-Compared to the dog, cats have a much higher bacterial load (108 vs. 104 organisms/ml) in the proximal small intestine. Thus, duodenal reflux may induce more pathology in the cat. Prior gastrointestinal tract disease also confers increased risk for the development of acute pancreatic necrosis in the dog. Unlike the cat, however, other risk factors, e.g., overweight body condition and endocrinopathies (diabetes mellitus, hyperadrenocorticism, hypothyroidism) also increase the risk of the disease. Pathogenesis--The acinar and ductal cells of the exocrine pancreas are interspersed between the islet cells of the endocrine pancreas. Like the endocrine pancreas, the exocrine pancreas is a secretory organ with several physiologic functions. Exocrine pancreatic fluid contains: digestive zymogens which initiate protein, carbohydrate, and lipid digestion; bicarbonate and water which serve to neutralize the duodenum; intrinsic factor which facilitates cobalamin (vitamin B12) absorption in the distal ileum; and, anti-bacterial proteins which regulate the small intestinal bacterial flora. Digestive zymogens are secreted primarily by acinar cells, while bicarbonate, water, intrinsic factor, and anti-bacterial proteins are secreted primarily by ductal cells. The two most common disorders of the exocrine pancreas, acute pancreatic necrosis and exocrine pancreatic insufficiency, are readily understood on the basis of these physiologic functions. With acute pancreatic necrosis, premature activation of digestive zymogen within pancreatic acinar cells leads to acinar cell necrosis (trypsin, chymotrypsin, carboxypeptidase), hemorrhage (elastase digestion of blood vessel elastin fibers), and fat necrosis and saponification (lipase digestion of pancreatic, peripancreatic and mesenteric fat). With exocrine pancreatic insufficiency, affected animals develop severe nutrient maldigestion, acid injury to the duodenal mucosa, cobalamin and fat soluble vitamin malabsorption, and small intestinal bacterial overgrowth. Pancreatic acinar cells protect themselves from intra-acinar activation of zymogen and acinar cell necrosis through several mechanisms: (1) Potentially harmful digestive enzymes are synthesized in the form of inactive precursors or zymogens in the rough endoplasmic reticulum. (2) Zymogens are then transported to the Golgi complex where they undergo selective glycosylations. Lysosomal hydrolases that are eventually packaged in lysosomes are separated from zymogens bound for export as they pass through the Golgi complex. Lysosomal hydrolases are first phosphorylated at the 6 position of mannose residues, bound to receptors specific for 6-phosphoryl mannose, and then transported to lysosomes where the acid pH favors their dissociation from the receptors. Digestive enzymes lack the 6-phosphoryl mannose label, and are instead transported vectorially into a different secretory fraction. (3) Packaging of zymogens into maturing zymogen granules sequesters them from contact with other sub-cellular fractions. (4) Pancreatic secretory trypsin inhibitor (PSTI) is incorporated into the maturing zymogen granules. PSTI inactivates trypsin should there be any intra-acinar activation of trypsinogen. (5) Following stimulation (e.g., feeding and cholecystokinin secretion), mature zymogen granules and their contents are released from the cell into the ductal lumen in a process of membrane fusion and exocytosis. (6) Finally, zymogens are activated physiologically only after they enter the duodenum, where the brush border enzyme enteropeptidase activates trypsinogen, and trypsin then activates other pancreatic zymogen. A large body of experimental (and some clinical) evidence suggests that 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

1 de 2

30-05-2008 10:43

Exocrine Pancreatic Disease - Proceedings - Library - VIN

http://www.vin.com/Members/Proceedings/Proceedings.plx?C...

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-, interferon-, interferon-, 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. Therapy--Supportive care continues to be the mainstay of therapy for feline acute pancreatitis. Thus, efforts should be made to identify and eliminate any inciting agents, sustain blood and plasma volume, correct acid/base and electrolyte disorders, place the pancreas in physiologic rest (NPO) for short periods of time, and treat any complications that might develop. Important complications of acute pancreatitis in cats include hypocalcemia, disseminated intravascular coagulation, thromboembolism, cardiac arrhythmia, sepsis, acute tubular necrosis, pulmonary edema and pleural effusion. Other therapies of benefit in the treatment of this disease include relief of pain (fentanyl, buprenorphine), anti-emetic agents (2 adrenergic antagonists, 5-HT3 antagonists), calcium gluconate supplementation, H2 histamine antagonists (to improve pancreatic blood flow), low dose dopamine infusion (5 g/kg/min; to improve pancreatic blood flow), and broad spectrum antibiotics (to reduce colonic bacterial translocation). High colonization rates suggest that bacteria may spread to the inflamed pancreas more frequently than is currently thought, and that broad-spectrum antibiotics may be appropriate in suspected cases of feline acute pancreatitis.

CHRONIC NON-SUPPURATIVE PANCREATITIS

Results of a recent study in our Hospital suggest that ante mortem differentiation of acute and chronic pancreatitis cannot be made based solely on clinical, clinicopathologic, or imaging findings. Many of the clinical criteria that clinicians have attributed to acute pancreatitis may also be seen in cats with histologically confirmed chronic pancreatitis. The prevalence of concurrent disease in both groups described in this study makes it difficult to determine if the nonspecific findings in history, physical examination, clinicopathologic and radiographic findings are attributable to acute or chronic pancreatitis. Although the absence of concurrent disease may suggest presentation with acute pancreatitis, histopathology remains the only dependable method of differentiating acute and chronic pancreatitis. In addition, the clinical relevance of differentiating acute and chronic pancreatitis with regard to morbidity, mortality, and outcome, requires further evaluation.

EXOCRINE PANCREATIC INSUFFICIENCY

Exocrine pancreatic insufficiency (EPI) is an uncommon cause of chronic diarrhea in cats. Insufficiency results from failure of synthesis and secretion of pancreatic digestive enzymes. The natural history of feline exocrine pancreatic insufficiency is poorly understood, but many cases are thought to result from chronic pancreatitis. As with dogs, clinical signs reported in cats with EPI include weight loss, soft voluminous feces, and greasy soiling of the hair coat. Affected cats may also have an antecedent history of recurring bouts of acute pancreatitis (e.g., anorexia, lethargy, vomiting) culminating in chronic pancreatitis and EPI. The diagnosis of EPI in cats has been technically difficult. Clinical signs in affected cats are not pathognomonic for EPI, clinicopathologic data are fairly non-specific, imaging findings are inconsistent, and the severity of pancreatic histologic changes are not always directly related to the severity of clinical signs. A feline-specific radioimmunoassay for trypsin-like immunoreactivity (TLI) has been developed, and a recent paper suggests that it may prove useful in the diagnosis of this disease. In that study, TLI concentrations less than 8 g/L (reference range = 17-49 g/L) were reported in 17/20 cats with clinical signs compatible with EPI (e.g., weight loss, loose voluminous feces, greasy soiling of the hair coat) and at least one other finding, e.g., decreased fecal proteolytic activity, exploratory laparotomy or necropsy findings compatible with EPI, or favorable response to pancreatic enzyme replacement therapy. References References are available upon request.

SPEAKER INFORMATION
(click the speaker's name to view other papers and abstracts submitted by this speaker) Robert J. Washabau, VMD, PhD, DACVIM Professor of Medicine Univ. of PA, School of Veterinary Medicine Philadelphia, PA

Front Page : Library : WVC 2004 : Small Animal : Gastroenterology : Exocrine Pancreatic Disease 800.700.4636 | VINGRAM@vin.com | 530.756.4881 | Fax: 530.756.6035 777 West Covell Blvd, Davis, CA 95616 Copyright 1991-2008, Veterinary Information Network, Inc.

2 de 2

30-05-2008 10:43