PANCREATITIS

From a clinical perspective pancreatitis can be broadly categorized as acute, recurrent acute, or chronic. it can be further classified according to its effect on the patient as mild or severe, nonfatal or fatal, and also by the presence of sequelae such as abscess formation.

Etiology and Pathogenesis

The etiology and pathogenesis of spontaneous pancreatitis is poorly understood. The major fac­tors that have been implicated (by association) as causes of acute pancreatitis in the dog and cat and the experimental evidence to support their involvement are summarized in Table 10-1.

Acute pancreatitis has only recently been con­sidered a significant disease entity in cats. it is my impression that pancreatitis in cats seems to be more chronically active and severe than in the majority of dogs. Although pancreatitis in cats has been diagnosed as the sole or predominant disease entity in cats at necropsy, it has also been vari­ably associated with diseases in other organs, for example, the liver (cholestasis, cholangiohepatitis, hydropic change, severe lipidosis), the kidney (mild to severe nephritis), the endocrine pancreas (diabetes mellitus), the lungs (pulmonary thrombosis), and the intestine (inflammation, ulceration).

Figure 10-1

Schematic diagram of the progression of acute pancreatitis. (From Simpson KW Lamb CR: Acute pancreatitis in the dog, In Practice: J Vet Postgrad Clin Study 17:328,1995.)

IV, Intravenous; CCK, cholecystokinin; GDV, gastric dilatation volvulus; FIP, feline infectious peritonitis.

a consequence of pancreatitis or are associated with disease processes that cause pancreatitis or are unrelated to pancreatitis is unclear at this time.

Irrespective of the initiating cause, pancreatitis is generally believed to occur when digestive enzymes are activated prematurely within the pan­creas. Experimental pancreatic hyperstimulation with cholecystokinin (CCK, or its analogue, cerulein), dietary supplementation with ethionine, and obstruction of the pancreatic duct lead to the formation of large intracellular vacuoles in acinar cells.Vacuole formation is thought to be a conse­quence of the uncoupling of exocytosis of zymo­gens and abnormal intracellular trafficking of digestive and lysosomal enzymes. These subcellular alterations are considered to precipitate the intracel­lular activation of digestive enzymes. Edematous pancreatitis induced by CCK hyperstimulation in dogs is characterized by a rapid but self-limiting burst of trypsinogen activation. It is of note that pancreatic necrosis in humans is associated with per­sistent trypsinogen activation, so it may be the abil­ity of the pancreas to limit trypsinogen activation that stops edematous pancreatitis from progressing to necrotizing pancreatitis.

Pancreatic hyperstimulation may also be of direct relevance to naturally occurring pancreati­tis in dogs and cats. CCK is normally released by cells in the duodenum in response to intraluminal fat and amino acids and coordinates and stimulates pancreatic secretion and gallbladder contraction during digestion. It is possible that high-fat diets exert their effects via the excessive release of CCK and that hypercalcemia, organophosphates, and high levels of circulating glucocorticoids also facilitate or cause pancreatic hyperstimulation; however, this is not proven.

Often pancreatic inflammation is a self-limiting process, but in some patients reduced pancreatic blood flow and leukocyte and platelet migration into the inflamed pancreas may cause progression to pancreatic necrosis. Secondary infection may arise by bacterial translocation from the intestine. Release of active pancreatic enzymes and inflam­matory mediators from the inflamed pancreas, such as tumor necrosis factor-α (TNF-α), inter­leukin-1 (IL-1), and phospholipid platelet activat­ing factor (PAF), amplifies the severity of pancreatic inflammation and adversely affects the function of many organs (systemic inflammatory response).

Further study of the cellular mechanisms gov­erning enzyme secretion and activation, leukocyte and platelet recruitment to the pancreas, bacterial translocation, and the development of the systemic inflammatory response in pancreatitis will hope­fully provide information that will be useful in treating acute pancreatitis in the patient population in the future.

Diagnosis

There is currently no single specific test for pan­creatitis in dogs and cats, and diagnosis is based on a combination of compatible clinical, clinico- pathologic, and imaging findings. Laparoscopic or surgical biopsy may be required to confirm a diagnosis and to distinguish inflammation from neoplasia.

Figure 10-2 The complex interactions of the complement, kinin, fibrinolytic, and coagulation pathways following activation of factor XII by contact or trypsin. Inhibitors are shown in italics. ATIII, Antithrombin III; a2M, alpha₂-macroglobulin; a-AT, alpha1-antitrypsin; C1-1A, complement fragment C1-1A. (Modified from Lasson A: Acute pancreatitis in man: a clinical and biochemical study of pathophysiology and treatment, ScandJ Gastroenterol 99:1,1984.)

Clinical Findings

Signalment and History

Dogs. Middle-age to old dogs (more than 5 years of age) that are overweight appear to be at higher risk. Miniature schnauzers, Yorkshire and Silky terriers, nonsporting breeds, and perhaps miniature poodles may be at increased risk of developing pancreatitis. There is no clear sex predisposition. Endocrinopathies such as hypothy­roidism, diabetes mellitus, and hyperadrenocortic- ism may also be risk factors.The history may reveal a recent episode of dietary indiscretion or drug administration.

Cats. Acute pancreatitis has been reported in cats from 4 weeks to 18 years of age. Domestic short and long hair cats are most commonly affected. Siamese cats have been overrepresented in some series. No sex bias has been demonstrated. A small number of cases have been associated with trauma, Toxoplasma gondii, pancreatic and liver flukes, feline infectious peritonitis (FIP), and lipodystrophy. Usually there are no obvious associated factors.

FIGURE 10-3 Inflammatory mediators in acute pancreatitis. Regardless of the inciting event (e.g., alcohol or gallstones), many poorly understood intracellular events lead to the development of acute pancreatitis.The progression of pancreatitis depends on several inflammatory mediators (interleukin [IL]-1, tumor necrosis factor [TNF], and platelet activating factor [PAF] are believed to be the most important). Other mediators (e.g., IL-6, IL-8, and nitric oxide [NO]) are produced, but they are markers of disease severity or regulatory proteins and are not mediators of disease progression. IL-1,TNF, and PAF stimulate the production of each other and mediate distant organ dysfunction such as adult respiratory distress syndrome (ARDS), hepatic dysfunction, shock, and death. DIC, disseminated intravascular coagulation; ATN, acute tubular necrosis. (From Denham W, Norman J:The potential role of therapeutic cytokine manipulation in acute pancreatitis, Surg Clin North Am 79:767,1999.)

The most common clinical findings in cats with acute pancreatitis are lethargy, anorexia, and weight loss. Vomiting, diarrhea, constipation, icterus, dehydration, ascites, and dyspnea are more variably present. Vomiting is not as prominent a sign of pancreatitis in cats as it is in dogs.

Physical Examination

Dogs. Physical findings in dogs with acute pan­creatitis are highly variable and range from depres­sion, to mild dehydration with signs of abdominal pain, to acute abdominal crisis with shock (tachy­cardia, prolonged capillary refill time, tacky mucous membranes, hypothermia), petechiation, icterus, and ascites. An abdominal mass is palpated in some dogs.

Cats. In cats dehydration and hypothermia have been most commonly observed. Icterus may also be present. Abdominal pain is infrequently elicited. The presence of a palpable cranial abdominal mass or abdominal pain has been reported in a quarter to a third of cats in some clinical series and in cats with experimental and trauma-induced pancreatitis.

Diagnostic Approach and Differential Diagnosis

Dogs. The differential diagnosis of acute pan­creatitis in dogs is usually centered around the problems of vomiting and abdominal pain (Box 10-1).

In vomiting dogs the initial approach is to dis­tinguish self-limiting from more severe causes of vomiting on the basis of physical findings and a minimum database (e.g., packed cell volume, total protein,blood urea nitrogen [BUN; e.g.,Azostick], urinalysis, plasma concentrations of sodium and potassium). Where vomiting is associated with sys­temic signs of illness, or is persistent, the clinician has to differentiate metabolic, polysystemic, infec­tious, toxic, and neurologic causes from intraab­dominal causes. This is usually achieved on the basis of combined historical and clinical findings coupled with a minimum database and the evalua­tion of hematology and serum chemistry profile, urinalysis, and abdominal radiography. Measurement

BOX 10-1

Differential Diagnosis of Pancreatitis in Dogs

Causes of Abdominal Pain

Gastric

Dilatation/volvulus, ulceration

Intestinal

Obstruction, intusussception, rupture, torsion, enteritis

Pancreatic

Pancreatitis

Hepatic

Acute hepatitis, ruptured bile duct, hepatic neoplasia

Splenic

Torsion, ruptured neoplasm

Urogenital

Nephritis, pyelonephritis, ruptured bladder, ureteral/urethral calculi, pyometra, prostatitis Peritoneum

Primary or secondary peritonitis (e.g., chemical: bile and urine, septic: ruptured viscus)

Pseudoabdominal Pain

Discospondylitis, prolapsed disk

Causes of Vomiting

Intraabdominal

Gastric

Gastritis, ulceration, neoplasia, outflow obstruction, foreign bodies, motility/functional disorders

Intestinal

Inflammatory bowel disease, neoplasia, foreign bodies, intussusception, torsion, rupture, bacterial overgrowth, functional disorders

Non-Gastrointestinal (Non-GI)

Pancreas: pancreatitis, pancreatic neoplasia

Liver: cholangiohepatitis, biliary obstruction

Genitourinary: pyometra, nephritis, nephrolithiasis,

Urinary: obstruction, prostatitis

Peritonitis

Metabolic/Endocrine

Uremia, hypoadrenocorticism, diabetic ketoacidosis, hepatic encephalopathy, hypercalcemia, septicemia

Drugs

Digoxin, erythromycin, chemotherapy, apomorphine, xylazine

Toxins

Strychnine, ethylene glycol, lead

Dietary

Indiscretion, intolerance, allergy

Neurologic

Vestibular disease, encephalitis, neoplasia, raised intracranial pressure

Infectious

Distemper, parvovirus, infectious canine hepatitis, leptospirosis, Salmonella

of serum amylase or lipase activity is often reported on routine serum chemistry profiles. Additional procedures such as ultrasonography, abdominal para­centesis, or pancreatic lipase immunoreactivity (PLI) assay are usually performed on the basis of these ini­tial test results and help to distinguish pancreatitis from other intraabdominal causes of vomiting.

Where abdominal pain is the major finding, localizing abnormalities such as abdominal disten­tion are rapidly pursued with radiography, ultra­sonography, and paracentesis. Concurrently, sup­portive treatment is provided on the basis of physi­cal findings and a minimum database while awaiting the results of hematology, serum chemistry profile, and urinalysis findings. Abdominal pain can arise from any intraabdominal structure. Musculoskeletal disorders such as discospondylitis and prolapsed disks can be hard to distinguish from abdominal causes of pain.

It is of note that diarrhea, which was bloody in some cases, was a more frequent sign than vomiting in dogs with experimental acute pancreatitis. Acute pancreatitis and its complications (infection, pseudo­cyst or abscess formation) should also be considered in the differential diagnosis of icterus and pyrexia. Some dogs with pancreatitis exhibit few localizing clinical signs. Diagnosis in these patients requires a high index of suspicion and use of versatile diagnostic tests such as ultrasonography.

Cats. In cats, lethargy, anorexia, and weight loss are the usual presenting complaints.Where encoun­tered, localizing signs or findings such as vomiting, icterus, diarrhea, abdominal pain, abdominal mass, polyuria, or polydipsia should be pursued. Because the antemortem diagnosis of acute pancreatitis is rarely made, its overall significance as a cause of these problems is unclear at this time.

Where vomiting is present, it is approached by pursuing localizing findings such as abdominal pain or masses and by ruling out infectious, para­sitic, metabolic, and gastrointestinal (GI) causes. Hyperthyroidism should be ruled out in older cats by determination of serum total thyroxine (T4) concentration. Elevated levels of hepatic enzymes, hyperbilirubinemia, hyperglycemia, and glucosuria are frequently encountered in cats with acute pan­creatitis, so pancreatitis should be strongly consid­ered in these cats.

The diagnostic approach to feline icterus is first to rule out prehepatic causes and then to pursue hepatic or posthepatic causes. The association of acute pancreatitis and hepatic lipidosis of increased mortality, cholangiohepatitis, and inflammatory bowel disease has been demonstrated in some studies. A high index of suspicion should be adopted for pancreatitis in cats with hepatic, bil­iary, or intestinal disease. Cats with a confirmed diagnosis of hepatic lipidosis and that have a peri­toneal effusion should also be strongly suspected of having pancreatitis.

Pancreatitis may be the cause of diabetes melli- tus in some cats, but the true association between these diseases is unclear. One study suggests that cats with pancreatitis and diabetes mellitus are very sensitive to insulin. Transient euglycemia and reduced insulin requirements after removal of a pancreatic abscess suggest that pancreatic inflam­mation or infection can exacerbate diabetes melli- tus in cats. Transient diabetes mellitus has also been reported in a cat that was suspected of having pancreatitis.

Where a high index of suspicion for pancre­atitis is present, ultrasonography and enzymology (assay of feline PLI) should initially be employed to help to detect pancreatitic inflammation. Pancreatic biopsy is required to achieve a definitive diagnosis.

Clinicopathologic Findings

Hematology

Dogs. Hematologic findings are highly vari­able, ranging from mild neutrophilia and slightly increased hematocrit, through marked leukocyto­sis with a left shift, to thrombocytopenia, anemia, and leukopenia with a degenerative left shift. If thrombocytopenia is detected, blood clotting tests (one stage prothrombin time [OSPT], activated partial thromboplastin time [APTT], fibrin degra­dation products [FDP or D-dimer]) are performed to determine if the patient has disseminated intravascular coagulation (DIC). Where available, the measurement of antithrombin III is useful in the early diagnosis of DIC.

Cats. A mild anemia that may be nonregen- erative and a leukocytosis that is usually not accompanied by a left shift are the most common findings in cats with pancreatitis.

Serum Biochemistry

Dogs. Serum biochemical abnormalities are variable and include azotemia (prerenal and renal), increased levels of liver enzymes (alanine amino­transferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [AP]), hyperbilirubinemia, lipemia, hyperglycemia, hypoproteinemia, hypocal­cemia, metabolic acidosis, and variable alter­ations (usually decreased) in sodium, potassium, and chloride.

Cats. Increased levels of ALT, AP, bilirubin, cholesterol, and glucose and hypokalemia and hypocalcemia are most common. Azotemia is variably present.

Urinalysis

Urinalysis enables azotemia to be characterized as renal or prerenal. Transient proteinuria occurs in some dogs with acute pancreatitis, possibly as a consequence of pancreatic enzyme-mediated glomerular damage. The absence of white cell casts or bacteria helps to rule out pyelonephritis as a cause of abdominal pain. The presence of glu- cosuria or ketonuria should prompt consideration of diabetes mellitus.

Pancreas-Specific Enzymes

Classically elevations in serum amylase and lipase activity have been used as indicators of pancreatic inflammation in dogs. However, these tests are not very accurate because dogs with nonpancreatic disorders may have elevated enzyme activities. This may occur because both amylase and lipase are normally present in other organs and their serum activities may increase with nonpancreatic disorders, including intestinal obstruction (amy­lase), corticosteroid administration (lipase), and renal disease (both enzymes). Dogs with con­firmed pancreatitis may also have normal amylase and lipase activity. For example, in two recent case series of dogs with histologically confirmed pan­creatitis, lipase was normal in 28 dogs (61%) and amylase was normal in 31 dogs (47%). This may be due to exhaustion of enzymes, thrombosis of pancreatic vessels, the presence of inhibitors, alterations in activity, and perhaps increased clear­ance. In cats it seems fair to state that measuring total amylase and lipase activity is of no utility for diagnosing pancreatitis.

These limitations have stimulated the develop­ment of assays for enzymes considered pancreatic in origin. TLI is one candidate. This species-specific immunoassay measures circulating trypsinogen in healthy individuals and trypsinogen and trypsin in those with pancreatitis.

In dogs, circulating TLI is abolished by pancre­atectomy and extremely low concentrations occur in EPI. Experimental and clinical studies have documented high concentrations of TLI in dogs with acute pancreatitis. TLI is therefore consid­ered a useful indicator of pancreatic mass and potentially inflammation. Nonpancreatic diseases such as renal disease and possibly corticosteroids may increase circulating TLI. It is important to note that the utility of TLI assay for the diagnosis of spontaneous pancreatitis in dogs has not been thoroughly evaluated, and I have observed both normal and subnormal concentrations in dogs with pancreatitis.

A TLI test has also been developed for cats. Cats with EPI and some cats with spontaneous pan­creatitis have abnormal concentrations of TLI. Increased application of this test indicates that high TLI concentrations may occur in the face of normal pancreatic histologic findings in cats with inflamma­tory bowel disease or lymphoma (Table 10-2).The reason for this is unclear. Nonpancreatic diseases such as renal disease and possibly corticosteroids may increase circulating TLI in cats.

At the present time it seems fair to conclude that the TLI assay is highly accurate for differenti­ating EPI from small intestinal disease. It appears less accurate in detecting pancreatitis. This is not surprising because pancreatitis is a very dynamic disease, which may influence the synthesis, secre­tion, elimination, and activity of circulating marker enzymes such as TLI. The tissue specificity of TLI makes it an attractive alternative to amylase and lipase activity tests in dogs, and it is presently the only useful indicator in the cat. The recent development of assays that measure pancreas spe­cific lipase in dogs and cats (cPLI and f PLI) has yielded promising initial results in helping to diag­nose pancreatic inflammation and may in time prove to be a useful diagnostic aid.

Radiography

Radiographic findings in cats and dogs with acute pancreatitis may include loss of serosal detail, increased opacity in the right cranial quadrant of the abdomen, displacement of the duodenum ven­trally and/or to the right, dilated hypomotile duo­denum, and caudal displacement of the transverse large intestine (see Chapter 2). Punctate calcifica­tion is occasionally identified in dogs with long­standing pancreatitis; it indicates saponification of mesenteric fat around the pancreas.

Although radiographic signs often are absent and are nonspecific, radiography remains a useful diagnostic method for pancreatitis largely because it may enable detection of other abnormalities that can cause similar signs (e.g., gastric foreign body or intestinal obstruction). Radiography is a logical first-choice imaging modality for patients with vomiting or abdominal pain. Negative or equivo-