Jörg M. Steiner, DrMedVet, PhD, DACVIM, DECVIM-CA, AGAF
Exocrine pancreatic insufficiency (EPI) is a condition that is caused by the insufficient synthesis and secretion of pancreatic digestive enzymes from the exocrine portion of the pancreas.
Disorders of the exocrine pancreas, and especially EPI, have traditionally been thought to occur less frequently in the cat than in dogs or humans. However, since the introduction of a new assay for the diagnosis of feline EPI, feline trypsin-like immunoreactivity (fTLI) in 1995, feline EPI is now diagnosed much more frequently than before. For example, of 180,648 cats entered into the Veterinary Medical Databases (VMDB), then at Purdue University, over a ten year period (from the early eighties to the early nineties), only 11 of those cats (0.006%) were reported to have been diagnosed with exocrine pancreatic insufficiency. In sharp contrast, in 2010, 775 cats were diagnosed with EPI through a severely decreased serum fTLI concentration measured at the GI Lab at Texas A&M University. This was up from 476 in 2008, 225 in 2004, and 23 cats in 2002. These data clearly show that EPI occurs with considerable frequency in cats, and also point to the fact that the recognition of EPI is still increasing.
Traditionally, EPI has been thought of as a condition of older cats. However, the age distribution of 882 cats, for which the age was known, with a serum fTLI concentration ≤ 8.0 µg/L assayed over a 5-year period, showed an even distribution of ages. Seven kittens were 6 months or younger, and 40 cats were 1 year of age or younger. A breed predilection has not been reported for feline EPI.
Etiology and Pathogenesis
In theory, there are many potential causes of EPI, including pancreatic aplasia, pancreatic hypoplasia, pancreatic acinar atrophy (PAA), pressure atrophy due to pancreatic duct obstruction, and pancreatic destruction due to pancreatic inflammation. However, most of these theoretical causes of EPI have never been described in a cat, and chronic pancreatitis is believed to be the most common cause of EPI in the cat. Three cases of pancreatic acinar atrophy in cats have been mentioned in the literature, but none of these cases have been reviewed in detail in the literature. A few cases of EPI without preceding pancreatitis have been reported due to Eurytrema procyonis infestation. Adenocarcinomas of the exocrine pancreas or other neoplastic lesions in the area of the pancreatic duct or the duodenal papilla can also lead to obstruction of the pancreatic duct, followed by atrophy of acinar tissue, but this has also never been reported in a cat. Another rare cause of pancreatic duct obstruction may occur due to proximal duodenal resection, when the major duodenal papilla is being damaged during surgery. Finally, congenital pancreatic hypo- or aplasia have also never been reported in a cat, but the author has seen one cat with evidence of pancreatic hypoplasia. The clinical syndrome of EPI does not require deficiency of all pancreatic digestive enzymes. For example, isolated pancreatic lipase deficiency has been reported as a rare cause of EPI in people and has also recently been reported in a single dog. However, isolated enzyme deficiency has not previously been reported in a cat.
In humans it has been shown that about 90% of the functional reserve of the exocrine pancreas must be lost before clinical signs of EPI develop. Digestive enzymes of pancreatic acinar origin play an integral role in assimilation of all major food components. A lack of pancreatic digestive enzymes will lead to maldigestion. The large amount of nutrients remaining in the intestinal lumen in cats with EPI usually lead to loose voluminous stools and steatorrhea. At the same time, the lack of nutrient assimilation will cause weight loss and may lead to vitamin deficiencies. Serum cobalamin (vitamin B12) concentrations are decreased in most cats with EPI. Serum folate concentrations in cats with EPI are either decreased, indicating concurrent small intestinal disease, or within the normal range. A cat with EPI with secondary vitamin K responsive coagulopathy has also been reported.
In cases of EPI, which are caused by chronic pancreatitis, destruction of pancreatic tissue may not be limited to the acinar cells, and concurrent diabetes mellitus may be observed. Diabetes mellitus has also been reported in cats with EPI. Thus, cats with diabetes mellitus that have a chronic history of loose stools should be evaluated for concurrent exocrine pancreatic disease.
Clinical signs most commonly reported in cats with EPI are polyphagia, weight loss, and loose stools. Naturally, these clinical signs are nonspecific and are also seen in many cats with other disorders that are more commonly seen in cats than EPI. The diarrhea is characterized by loose or semiformed voluminous stools, which may have a yellow- to clay-colored appearance, and may be quite malodorous. Some cats with EPI may develop watery diarrhea, but this is not common. The high-fat content of the feces can lead to a greasy appearance of the hair coat of the cat, especially in the perianal and tail region. However, in a recent report of 20 cats with EPI, only a single cat showed greasy soiling of the haircoat in the perineal region.
Recently, a cat with severe D-lactic acidosis with clinical signs of episodic generalized weakness, ataxia, and lethargy was shown to be due to secondary to EPI. The authors speculated that the D-lactic acidosis was due to massively increased bacterial fermentation in the intestinal lumen due to small intestinal bacterial overgrowth secondary to EPI. The D-lactic acidosis and associated clinical signs resolved after enzyme supplementation of this cat. As mentioned above, some cats may have concurrent diabetes mellitus and may thus be presented with PU/PD or even with acute complications of diabetic ketoacidosis. Also, patients may show residual signs of chronic pancreatitis, such as anorexia or abdominal discomfort. Similarly, many cats with chronic pancreatitis have concurrent inflammatory conditions of other abdominal organs, such as the intestines or the liver, and may show clinical signs associated with those inflammatory conditions.
Results of routine blood tests are within the normal range in most cases. In a few cases, lymphopenia, lymphocytosis, neutrophilia, eosinophilia, and elevations of hepatic enzymes have been reported. It is unclear from the literature whether these changes are rare changes associated with EPI or, more likely, are associated with concurrent conditions, such as diabetes mellitus, inflammatory bowel disease, or chronic cholangitis. Abdominal radiographs or ultrasound also do not show any specific changes in most cats with EPI. More common are radiographic and/or ultrasonographic changes that are due to concurrent conditions.
As mentioned above, EPI is a functional disease and thus requires a functional diagnosis. Several tests have been recommended to estimate exocrine pancreatic function in cats. The bentiromide absorption test, commonly known as PABA test, plasma turbidity, microscopic examination of feces for undigested fat, starch, or muscle fibers, and fecal proteolytic activity (FPA), all have been recommended for the use in cats. With the exception of FPA, all of these tests are unreliable and/or impractical in cats and are not recommended. Also, FPA is very labile, and false positive results can occur due to inappropriate sample handling. At least three stool samples from consecutive days should be evaluated. Feces need to be frozen immediately and shipped on ice in order to prevent loss of FPA in the samples. Better diagnostic tests for feline EPI are now available, and FPA should only be used for species for which such more modern tests are not available.
An assay for the measurement of feline trypsin-like immunoreactivity (fTLI) concentration has been developed and analytically validated. This assay has been fully analytically validated, and the current reference range is 12.0–82.0 µg/L, with values of ≤ 8 µg/L being considered diagnostic for EPI. The assay for fTLI quantifies the amount of trypsinogen in the serum. When the pancreas is stimulated to secrete digestive enzymes, zymogen granules are released into the pancreatic duct system by way of exocytosis. However, a small amount of zymogen granules are being released into the vascular bed. The trypsinogen released can be measured in the serum with the fTLI assay.
Recently, it was shown that decreased renal function has a significant effect on serum fTLI concentrations and cats with renal failure may have falsely increased serum fTLI concentrations. Therefore, evaluation of serum fTLI concentrations in azotemic cats may obscure a diagnosis of feline EPI. However, no cases have as of yet been identified where a diagnosis of EPI was missed because of renal failure. The author would suggest to re-evaluate serum fTLI concentrations in azotemic cats that have a borderline fTLI concentration and in whom an alternative diagnosis for loose stools and weight loss cannot be identified. In contrast to dogs, serum fTLI did not significantly increase after feeding of healthy cats. However, this was not studied in cats with suspected EPI. Thus, the current recommendation is to withhold food from cats for 12 hours before collecting a sample for measurement of serum fTLI concentration, whenever possible.
Most cats with EPI can be successfully managed by dietary supplementation with pancreatic enzymes. Dried extracts of porcine pancreas are available (e.g., Viokase® or Pancrezyme®), but raw beef, pork, or game pancreas can also be given instead. If commercial products are used, powder is more effective than tablets or capsules. Initially, one teaspoon per meal should be given. As cats often don't like the taste of the pancreatic powder, it is best to thoroughly mix the powder with some canned food. If the cat refuses to consume the food with the powder, it can also be mixed with fish oil and then mixed into the food. If raw pancreas is used, it should be chopped, portioned, and frozen in packages for one meal each. Fresh frozen pancreas can be kept frozen for several months without losing effectivity. One to two ounces (30–60g) of raw chopped pancreas should be given per meal.
Preincubation of the food with pancreatic enzymes or supplementation with bile salts are not necessary. Most cats respond quite rapidly to enzyme replacement therapy and show resolution of loose stools within 3–4 days. When clinical signs have resolved, the amount of pancreatic enzymes given with each meal can be gradually decreased to the lowest effective dose, which may vary from patient to patient, and may also vary between different batches of the pancreatic supplement.
Response to enzyme supplementation alone may not be satisfactory in some patients. This is not surprising if one considers that many cats with EPI have cobalamin deficiency and cobalamin deficiency can lead to gastrointestinal and systemic clinical signs. It is thus crucial to correct cobalamin deficiency in all cats with a decreased or low-normal serum cobalamin concentration. Since cobalamin deficiency causes cobalamin malabsorption, oral supplementation is not effective in patients with cobalamin deficiency. Also, multivitamin preparations do not contain sufficient amounts of cobalamin, and pure cobalamin is needed for therapy. In cats, 250 µg is given subcutaneously per injection. An injection is given once a week for 6 weeks, followed by an injection every other week for 6 weeks, one more dose a month after that, and a recheck a month after the last dose. Vitamin status for other vitamins has not been systemically evaluated in cats with EPI. However, if the cat shows bleeding tendencies, a coagulation profile should be evaluated and, if indicated, the cat be treated with vitamin K. To date, only one cat with EPI and a vitamin K-responsive coagulopathy has been reported.
Even patients that completely respond to enzyme therapy do not have a completely normalized fat absorption. This is most likely due to the fact that a portion of the pancreatic lipase of the supplement is being irreversibly denatured by the low pH in the stomach. This is probably the reason why some clinicians recommend feeding a low-fat diet to patients with EPI. However, decreasing the fat content of the diet also decreases the supply of fat-soluble vitamins and essential fatty acids, potentially leading to deficiencies of these essential nutrients. Thus, the author does not recommend to routinely decrease the fat content in the diet for cats with EPI. Several studies have evaluated the impact of diet on treatment success in dogs with EPI, and none of these studies were able to show any impact of diet. While there are no studies available for cats, there are no specific dietary recommendations for cats with EPI. However, the author believes that it is prudent to avoid high-fiber diets, as fiber may further hinder the digestion of fat.
Cats that fail to respond to therapy may benefit from treatment with an antacid. A proton pump inhibitor (e.g., omeprazole at 0.7 mg/kg q12h) would be expected to provide the most consistent gastric pH control. This may decrease the degree of irreversible inhibition of exogenous pancreatic lipase in the stomach.
Some cats will not respond appropriately to enzyme supplementation and cobalamin application. These cats may have concurrent small intestinal disease. Such patients may benefit from antibiotic therapy, such as tylosin at 25 mg/kg q12h or metronidazole at 15–25 mg/kg q12h.
Most cats with EPI have an irreversible loss of pancreatic acinar tissue and thus exocrine pancreatic function. Recovery is extremely rare and is poorly understood. However, with appropriate management and monitoring, these patients usually gain weight quickly, pass normal stools, and can go on to live a normal life for a normal life span.