Feline pancreatitis: underdiagnosed or overdiagnosed? (Proceedings)

For years, feline pancreatitis has been assumed to be a similar disease to that in dogs. As with so many other disorders, this group of disorders is different in the cat. Given that the term "pancreatitis" implies nothing more than inflammation of that organ, it is not surprising that each species may have a variety of etiologies. In a German retrospective study, the prevalence of pathologically significant lesions in dogs was found to be 1.5% and in cats, 1.3% of the specimens submitted. Indeed, there are papers reporting the incidence as high as 2.9 and 3.5% of necropsied cats. More recently (2007), in a retrospective study evaluating the prevalence and histopathologic features of pancreatitis in the pancreata of 115 cats presented for necropsy for any reason, the stunning finding of prevalence of histologic evidence of pancreatitis in all of these cats was 67% and, even more astounding is the finding of a 45% prevalence in cats who were apparently clinically normal at the time of death! [DeCock]

Human medicine classifies pancreatitis as acute or as chronic. Using a similar scoring system, the aforementioned study determined that in cats, acute pancreatitis (AP) consists of neutrophilic inflammatory changes with concurrent interstitial edema and mesenteric fat necrosis. In chronic pancreatitis (CP) fibrosis is more notable than is inflammation, and the inflammatory cell infiltrate favours lymphocytes along with some macrophages and eosinophils. Additionally, cystic dilation and changes in lobulation were seen in the chronic form of the disease. Unlike human CP, there were only minimal pancreatic duct changes in cats.

From a clinical standpoint, AP is a short term, disease, often completely reversible unless it is acute necrotizing disease, which is a completely different entity. Because chronic pancreatitis, the more common form of pancreatitis in cats, represents a long-term process and is associated with irreversible histopathological changes, primarily fibrosis it isn't curable; however, it can generally be controlled and is less fatal than acute necrotizing pancreatitis (ANP). Although unproven, there is some thought that CP may ↔ ANP in some cases. [Washabau]

Both acute and chronic pancreatitis can be mild or severe, but acute cases tend to be more severe, and chronic cases milder. Mild pancreatitis generally results in minimal clinical signs, minimal necrosis, and low mortality.

In acute necrotizing pancreatitis, (ANP) extensive pancreatic necrosis and multiple organ involvement +/- organ failure are seen. Fortunately, because in cats this form is rare, severe multi-system complications are uncommon. The prognosis for acute necrotizing pancreatitis is poor. Other complications of pancreatitis may include fluid accumulation around the pancreas, infection of necrotic areas, pseudocysts, and abscesses.[Bailiff] [Coleman]

Histopathologic classification may help in designing appropriate therapeutic protocols for our patients. DeCock paper suggests one schema and is found online at: http://vet.sagepub.com/content/44/1/39.full.pdf+html. When you submit pancreatic biopsies be sure to get a good description from your pathologist.

In the majority of cases, the etiology is unknown. Some contributory factors include the following:

1. More than > 90% of the cases of feline pancreatitis are idiopathic.

2. Anything causing ischemia to the organ. "The most pivotal determinant in the development and progression of pancreatitis is likely the maintenance of local blood flow. Ischemia favours progression to an auto-digestive state; impairment of the microcirculation results in retention of activated enzymes, depletion of anti-proteolytic proteins, and reduced removal of toxic products. Necrosis of the gland follows pancreatic ischemia, leading to a self-perpetuating cycle of damage." (Center SA, Proceedings of AAFP 2000 Fall Meeting)

3. Traumatic pancreatitis has been reported in a few cats associated with vehiclular accidents or high-rise syndrome.

4. Several infectious agents have been implicated including feline parvovirus, Toxoplasma organisms (of 45 pancreata examined in 100 cats infected with Toxoplasma, 38 had lesions), feline herpesvirus I, Eurytrema procyonis (racoon pancreatic fluke)[Vyhnal], feline infectious peritonitis (FIP), and, rarely, Amphimerus pseudofelineus.

5. Feline pancreatitis was reported in 2 cats following topical fenthion administration (organophosphate intoxication is a common cause of pancreatitis in children in underdeveloped countries).

6. Experimentally, pancreatic duct infusion of oleic acids or infected fluids have induced pancreatitis in experimental models; the latter may be reflected in some cases of "triaditis".

7. Drugs have been implicated as causing pancreatitis in humans and dogs but not yet in cats. Drugs associated with pancreatitis in humans include azathioprine, chlorothiazide, hydrochlorothiazide, estrogens, furosemide, tetracycline, sulfonamides, L-asparaginase, 6-mercaptopurine, methyldopa, pentamidine, nitrofurantoin, dideoxyinosine, valproic acid, and procainamide.

As the De Cock study speculates, one reason for the high prevalence of CP in cats unrelated to age may be that the pancreas is very sensitive to drugs, stress, metabolic derangements, or ischemia associated with a wide variety of clinical conditions. Anaesthesia-related hypoperfusion or hypovolemia from any cause might also result in ischemia.

Pathogenesis: It is believed that various noxious stimuli can cause the exocrine pancreas to decrease the secretion of pancreatic enzymes, followed by the formation of cytoplasmic vacuoles with the co-localization of proenzymes of digestive enzymes and lysosomal enzymes. Normally the lysosomal enzymes are strictly segregated from proenzymes to prevent premature activation of the proenzymes. A decreased pH along with the loss of segregation of the lysosomal enzymes and proenzymes cause abnormal intrapancreatic activation of trypsinogen which when activated to trypsin activates other proenzymes resulting in a local and systemic inflammatory response in ANP. Whether this is the same mechanism in cats or not has not, to the author's knowledge, been determined. The pathogenesis of AP and CP is not understood and is side-stepped in the literature.

Clinical findings: Pancreatitis should be included in a diagnostic rule-out list whenever there is a history of lethargy, anorexia, dehydration, hypothermia, vomiting (in only 35% in one paper), abdominal pain, abdominal mass effect, dyspnea, diarrhea and ataxia. Concurrent problems may include hepatic lipidosis, cholangitis/cholangiohepatitis, idiopathic inflammatory bowel disease, enteritis, diabetes mellitus, and vitamin K1 responsive coagulopathy. Triaditis, (enteritis, cholangitis and pancreatitis) appears to be more common than any of these component conditions on its own. Clinical findings for pancreatitis are, therefore, extremely vague and a diagnosis is achieved through a combination of clinical suspicion, abdominal ultrasound findings and feline pancreatic lipase immunoreactivity (fPLI) [Zoran].

The incidence of concurrent, non-pancreatic pathology in 40 cats with ANP revealed fluid in third spaces in 47% (19/40) cats. Hepatic changes included lipid accumulation in 47% (19/40), necroinflammatory changes in 15% (6/40). Intestinal lesions were seen in 32% (13/40), interstitial nephritis in 42% (14/40), pulmonary changes consisting of pneumonia, bronchitis and/or edema in 5% (2/40), 5% (2/40) and 820% (8/40) respectively. Finally, thrombosis was identified in 20% (8/40) and hemorrhagic tendencies in an additional 15% (6/40) of these cats on necropsy. [Hill]

A retrospective study published in 2003 looked at 63 histologically confirmed cases of feline pancreatitis to see what differences there are between acute necrotizing and chronic nonsuppurative forms of pancreatitis. "Results suggest that ANP and CP in cats cannot be distinguished from each other solely on the basis of history, physical examination findings, results of clinicopathologic testing, radiographic abnormalities, or ultrasonographic abnormalities." Histology (and/or cytology) are needed. [Ferreri]

Diagnostics: Given the poor predictive value of any clinical finding in achieving the diagnosis, we must rely on a combination of examination, imaging, biochemical changes and ultimately tissue evaluation (cytology and/or histopathology).

Regarding imaging: The classical signs of abdominal tenderness or mass in the right anterior quadrant along with haziness in this region and displacement of abdominal viscera on abdominal radiographs and/or visualization of a (nodular) hyperechogenicity or peripancreatic fluid or a pancreatic abscess or mass on ultrasound examination support the presumptive diagnosis of pancreatitis.

1) Radiographic findings reportedly include reduced contrast in the cranial abdomen, localized dilatation of small intestinal loops, displacement of abdominal organs with the duodenum often moved dorsally and laterally, the stomach moved to the left, and the transverse colon caudally.

2) Ultrasonographic findings may include the following changes in the pancreas — swelling, increased echogenicity, mass effects, and fluid accumulation around the pancreas or there may be no ultrasonographic changes. Abdominal ultrasound is sensitive in cats with moderate-severe pancreatitis and specific (reliable negative predictive value) in healthy cats. [Forman] Two studies have been done to assess the effects of age on the normal pancreas and pancreatic duct. Both have shown that pancreatic size and echogenicity do not change with age, and that pancreatic duct diameter increases with age. A dilated duct should not be used as the definitive indicator of pancreatitis in an elderly cat. [Moon Larson] [Hecht]

3) A study was performed to evaluate the usefulness of endosonography as a tool for diagnosing pancreatitis. The conclusion was that this technique did not alter the diagnosis in the six cats with pancreatitis or the 11 normal cats when compared to abdominal ultrasound. It is a technique that may be useful when ultrasound is limited by obesity, intestinal gas or a hyperechoic mesentery. [Schweighauser]

4) Contrast-enhanced computed tomography (CT) is used in humans to diagnose and stage the severity of pancreatitis with its ability to detect and delineate areas of necrosis. In cats, especially with contrast enhancement may improve diagnostic acuity in cats. [Head]

Of the imaging modalities most readily available, ultrasound is the most sensitive, non-invasive evaluative tool that we have at this time.

Regarding serum biochemistry and hematology: In general, changes are most commonly mild and nonspecific. There may be mild, non-regenerative anemia in chronic pancreatitis or a severe anemia terminally in acute, necrotizing pancreatitis. An inflammatory or stress leukon may be present, and in the case of a pancreatic abscess or a suppurative pancreatitis, a left shift may be seen. Concurrent elevations of SAP and ALT are not uncommon and reflect inflammatory or lipidotic involvement of adjacent tissue. Nonspecific changes, such as hyperglycemia (stress or concurrent diabetes), hypocalcemia, hypokalemia (innapetence), hypercholesterolemia, azotemia (prerenal and/or renal), and hyperbilirubinemia have all been reported. Hypoalbuminemia may be present in moderate-severe pancreatitis.[Forman] The lack of sensitivity and specificity of amylase and lipase is a source of frustration in diagnosing feline pancreatitis. The lack of hyperlipasemia cannot be depended on to rule-out pancreatitis. Elevations in serum amylase may occur not only with pancreatitis, but more commonly from other gastrointestinal diseases, as well as from decreased renal clearance of this enzyme.

TLI has been shown to be diagnostic for severe acute pancreatitis. However, this does NOT detect the more common, chronic and milder forms of pancreatitis. Trypsinogen and trypsin are pancreas-specific in origin, and both are detected by the trypsin-like immunoreactivity (TLI) assay. TLI test is very specific but NOT sensitive. Even though published reference intervals are 17-48 micrograms/dl values under 150-200 are equivocal. TLI seems most reliable in identifying acute pancreatitis. Later in the course of disease it may not be elevated because either the sick pancreas has leaked all of the enzymes that it had made and isn't capable of producing more (after several days of inflammation) or the pancreatic blood flow has decreased following the worst phase of the inflammatory response. Mild inflammation may also just not stimulate much leakage of enzyme. So, early on in pancreatitis you are most likely to get an abnormally high result.

Feline pancreatic lipase immunoreactivity (fPLI) has been shown to be sensitive in cats with moderate-severe pancreatitis as well as having a high negative predictive value (i.e., specific) in healthy cats. [Forman] Things one must be aware of when using this test is that it has high interassay variability, meaning that results may vary significantly from run to run. This limits its usefulness for monitoring therapeutic efficacy as well as reliability in making a diagnosis. It is most reproducible in its middle range. The other concern is that observed: expected ratios are very wide. An observed:expected ratio describes the amount of a substance recovered when a known amount is utilized. Ideally, a test "should" detect 100% of a substance it is measuring (O:E = 1). The O:E for when a known amount of pancreatic lipase was added in various concentrations to feline serum, ranged from 76.9% (not picking it all up) to 147.6% (picking up more than was added). [Steiner] The levels of fPLI concentrations have been evaluated in cats with diabetes mellitus in one study. This report found that cats with diabetes had higher fPLI levels than cats without diabetes. This increased fPLI value was unrelated to the degree of control of the diabetes and interestingly, there were no significant differences in reported clinical signs between cats with or without DM regardless of serum fPLI concentration. [Forcada]

Cobalamin levels may be subnormal in cats with pancreatitis because, in this species, the pancreas is the only known source of intrinsic factor. Intrinsic factor is complexed to dietary cobalamin, absorbed into the body, be transferred to transcobalamin proteins, and then finally enter cells. [Ruaux] A future diagnostic parameter may include evaluation of serum amyloid A concentration as it has been reported in one case to be a useful marker for evaluating response to therapy and disease reoccurrence. [Tamamoto]

Regarding definitive diagnosis: Ultimately, surgical biopsy is required to make the histopathological diagnosis. Whilst dogma was that biopsying the pancreas is a pathophysiologically dangerous undertaking, in the cat, this does not appear to be the case. The author routinely biopsies the pancreas in all of her exploratory patients. Ultrasound guided aspiration of the pancreas is a less invasive tool which may also yield useful clinical clues. Gently isolate the pancreas from the surrounding viscera and pack it off with a moistened gauze swabs being careful to not exteriorize the organ. Doing this results in rapid, dramatic hypotension. Using fine scissors (e.g., iris scissors), take a 4 X 4 mm wedge from both poles as well as any gross lesion. Submit a small piece in a culture medium as well as formalin preserved samples, in case the lesion is reported as septic suppurative.

Therapy: Therapy for pancreatitis is best designed about the form/class of pancreatitis. Fluid therapy and pain relief are the cornerstones in supportive care. Fluids sustain blood and plasma volume and blood pressure to ensure adequate perfusion and to correct acid-base and electrolyte disorders. Pain control must be addressed. Assume there is pain and plan accordingly. Analgesia is of critical importance in the comfort of the patient, but also in the progression of the disease/inflammation through the negative physiological effects of pain. Pain causes disease and prevents healing. Even if obvious abdominal pain isn't present, a test dose of 0.1-0.2-mg/kg oxymorphone IV or buprenorphine IV, SC may be considered to see if the patient improves over the approximately 6 hour effective period. If that is the case, then constant rate infusion of a narcotic may be considered or a transdermal fentanyl patch (Duragesic™) for continuous relief. Torbugesic™ is not as effective for visceral pain as the opioid agonists are.

NSAIDs may be selected for their usefulness both as anti-inflammatory agents as well as their analgesic component. As always, adequate hydration of a patient, knowledge of appropriate renal function and the lack of gastrointestinal bleeding are important before choosing this class of drugs. Use of COX-2 inhibitors minimizes the risk to feline patients as does appropriate dosing and dosing intervals.

Concurrent problems (such as lipidosis or enteritis) should be addressed as well. A noteworthy difference between the dog and cat is the recommendation to feed, rather than fast, those patients suspected of (or confirmed as) having pancreatitis unless they are vomiting. Even with the vomiting cat, designing a nutritionally supportive protocol is of great importance due to this species' ease of developing lipidosis. The author fasts cats for no longer than 24 hours utilizing anti-emetics as necessary. In these few intractably vomiting cats, total parenteral nutrition or jejunostomy tube feeding may be advisable for 7-10 days. Discussion of tube feeding (nasogastric, esophageal, gastrotomy, jejunostomy) may be found in numerous texts, and therefore won't be discussed here. Trickle feeding may be of value when emesis persists despite pharmacologic intervention.

When the use of anti-emetics is being considered, bear in mind that as these agents are metabolized by the liver their clearance rates may be decreased. Doses should be reduced accordingly. Anti-emetics commonly used in the cat include metaclopromide (Reglan™) and chlorpromazine (Largactil™). Each of these drugs also has its own, inherent side effects, such as the central nervous system (CNS) sedation or frenzied behaviour or disorientation of Reglan™ in the cat or the hypotensive effect of the Largactil™. Zofran™ while costly, is very beneficial in the intractably vomiting patient. Mirtazapine is very useful due to the infrequency of administration as well as its potential appetite stimulating effects. Maropitant (Cerenia™) is effective in many cats

Table 1: List of Anti-emetics for Use in the Cat

In the past, it was suggested that bland, low fat, high carbohydrate diets are most suitable however, there is no research done to support this recommendation that the author is aware of. Cats, being obligate carnivores, don't normally utilize carbohydrates well. The goal should be to feed a balanced, non protein-restricted diet. Ensure that the cat receives 50 kcal/kg ideal weight/day.

Modification of gastric acidity has been advised; the gastric pH can be checked by measuring pH of vomitus or by gastric suctioning. An H2 blocker, such as famotidine (0.5 mg/kg PO, IV q24h) or a proton pump inhibitor, such as omeprazole (0.5-1.0 mg/kg PO q24h) may be used. Symptomatic treatment using antimicrobials against anaerobic and gram-negative enteric opportunists is recommended. If specific pathogens are identified from a pancreatic abscess or other samples, the antimicrobial drugs can be chosen based on gram stain, initially, and, ultimately, the sensitivity pattern. While pancreatic enzymes are not indicated other than in the rare case of feline exocrine pancreatic insufficiency, They are used in some human pancreatitis patients in order to reduce pain through feedback to the pancreas inhibiting further enzyme release (and leakage). Whether this is the case in cats (or dogs) isn't known. Antibiotics are indicated if the diagnosis of a suppurative pancreatitis has been made. In this case, antimicrobial selection is best made with the knowledge of a sensitivity spectrum. Note that a suppurative pattern may be seen on histology in a sterile pancreatitis caused by enzyme damage. In patients with ANP, broad-spectrum antibiotics should be utilized to prevent bacterial translocation. Corticosteroids are indicated if a lymphocytic/plasmacytic form is reported or in an acute shock presentation. No benefits have been seen with the use of anticholinergics, GI hormones (somatostatin, glucagon), or calcitonin. Dopamine has been useful in acute experimental feline pancreatitis.

Fresh frozen plasma may be considered in cats with severe pancreatitis to replace plasma proteases, albumin and alpha 2 macroglobulins. For most cats with pancreatitis, the attempt is made to reduce inflammation and fibrosis. Prednisolone +/- metronidazole are warranted for this. An interesting case report [Sakai] describes using a synthetic protease inhibitor in addition to these agents. Its action is to inhibit thrombin, plasmin, trypsin and other agents.

The prognosis depends on the type, duration and severity of the disease. Many cats have chronic, low-grade smoldering pancreatitis and live long lives, but do better with diagnosis and appropriate therapy.

References

Bailiff NL, Norris CR, Seguin B, et al: Pancreatolithiasis and pancreatic pseudobladder associated with pancreatitis in a cat. J Am Anim Hosp Assoc. 40(1):69-74, 2004.

De Cock HEV, Forman MA, Farver TB, et al: Prevalence and histopathologic characteristics of pancreatitis in cats. Vet Pathol. 44(1): 39-49, 2007.

Coleman M, Robson M: Pancreatic Masses Following Pancreatitis: Pancreatic Pseudocysts, Necrosis, and Abscesses. Compend Contin Educ Pract Vet. 27(2):147-154, 2005.

Ferreri JA, Hardam E, Kimmel SE, et al: Clinical differentiation of acute necrotizing from chronic nonsuppurative pancreatitis in cats: 63 cases (1996-2001). J Am Vet Med Assoc. 223(4): 469-74, 2003.

Forcada Y, German AJ, Noble PJM, et al: Determination of serum fPLI concentrations in cats with diabetes mellitus. J Feline Med Surg. 10(5):480-7, 2008.

Forman MA, Marks SL, De Cock HEV, et al: Evaluation of serum feline pancreatic lipase immunoreactivity and helical computed tomography versus conventional testing for the diagnosis of feline pancreatitis. J Vet Intern Med. 18(6): 807-15, 2004.

Head LL, Daniel GB, Becker TJ, et al: Use of computed tomography and radiolabeled leukocytes in a cat with pancreatitis. Vet Radiol Ultrasound. 46(3): 263-6, 2005.

Hecht S, Penninck DG, Mahony OM, et al: Relationship of pancreatic duct dilation to age and clinical findings in cats. Vet Radiol Ultrasound. 47(3):287-94, 2006.

Moon Larson M, Panciera DL, Ward DL, et al: Age-related changes in the ultrasound appearance of the normal feline pancreas. Vet Radiol Ultrasound. 46(3):238-42, 2005.

Ruaux CG: Cobalamin And Gastrointestinal Disease. In: Proceedings ACVIM 2002.

Sakai M, Harada K, Matsumura H, et al: A case of feline pancreatitis. J Vet Med Sci. 68(12):1331-3, 2006.

Schweighauser A, Gaschen F, Steiner JM, et al: Evaluation of endosonography as a new diagnostic tool for feline pancreatitis. J Feline Med Surg. 11(6): 492-8, 2009.

Steiner JM, Wilson BG, Williams DA: Development and analytical validation of a radioimmunoassay for the measurement of feline pancreatic lipase immunoreactivity in serum. Can J Vet Res. 68(4): 309-14, 2004.

Tamamoto T, Ohno K, Ohmi A, et al: Time-course monitoring of serum amyloid A in a cat with pancreatitis. Vet Clin Pathol. 38(1):83-6, 2009.

Vyhnal KK, Barr SC, Hornbuckle WE, et al: Eurytrema procyonis and pancreatitis in a cat. J Feline Med Surg. 10(4): 384-7, 2008.

Washabau RJ: Feline Pancreatic Disease. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, ed 7, St. Louis, 2010, Elsevier, p 1704-1709.

Zoran DL: Pancreatitis in cats: diagnosis and management of a challenging disease. J Am Anim Hosp Assoc. 42(1): 1-9, 2006