Canine and Feline Exocrine Pancreatic Insufficiency

Exocrine pancreatic insufficiency (EPI) is a malabsorptive disease caused by insufficient secretion of digestive enzymes from the pancreatic acinar cells. There are many potential causes of EPI; however, pancreatic acinar atrophy (PAA) appears to be the most common cause of disease in dogs and typically presents at a young age.¹ Damage to the exocrine pancreas from chronic pancreatitis appears to be prevalent in cats, leading to a variable age of onset, although PAA is also reported.² Other potential causes of EPI include pancreatic duct obstruction, pancreatic neoplasia, and liver flukes (cats).

EPI results from a deficiency of pancreatic enzymes secondary to damage to the pancreatic acinar cells. Clinical signs of EPI do not develop until more than 90% of acinar cells are lost.³ Insufficient digestive enzymes result in maldigestion of dietary components, leading to malabsorption and subsequent nutrient and calorie deficiency. Nondigested materials within the intestinal lumen contribute to osmotic diarrhea.

EPI Breed Predispositions

While any dog or cat can develop EPI, breed predilections have been reported in the German shepherd, rough collie, English setter, Cavalier King Charles spaniel, and Chow Chow.⁴ Breed predilections are not reported in cats.

Diagnostic Approach to EPI

Clinical Presentation

Dogs with PAA may be subclinical at the time of diagnosis, particularly in predisposed breeds when active screening is performed. However, many dogs are diagnosed only after the development of clinical signs, which may include weight loss despite a good appetite, steatorrhea, and poor coat quality.⁵ Some dogs also present with flatulence and abdominal discomfort. Dogs with EPI associated with chronic pancreatitis may demonstrate waxing and waning gastrointestinal (GI)upset and pain.⁶

The clinical signs of EPI in cats can be subtle and nonspecific⁷; therefore, it is easy to miss a diagnosis of EPI in a cat unless active steps are taken to screen for the disease. The most common clinical sign of EPI in cats is weight loss, often in the absence of an increased appetite.⁷ Other clinical signs include diarrhea, vomiting, anorexia, weakness, and poor coat quality.^7,8 Rarely, a coagulopathy may be present due to vitamin K deficiency.⁹

Potential diagnostic differentials for EPI are listed in TABLE 1.

Trypsin-Like Immunoreactivity

The diagnosis of EPI relies on quantification of species-specific trypsin-like immunoreactivity (TLI), which is the gold-standard diagnostic test for EPI in both dogs and cats.¹⁰ Low TLI concentrations are consistent with a diagnosis of EPI. Fortunately, because TLI concentrations are species specific, they are not affected by pancreatic enzyme supplementation, which is typically porcine in origin. Therefore, TLI can still be measured in animals that were started on pancreatic enzymes prior to obtaining a definitive diagnosis.

A “gray zone” (equivocal) TLI concentration is one that is below the reference interval but not yet below the diagnostic cutoff for EPI. The diagnostic gray zone is defined by each laboratory. If a TLI concentration is in the gray zone, other causes of related clinical signs should be ruled out and testing repeated on a fasted sample in 1 to 2 months.¹¹

If clinical suspicion for EPI in a dog is high and repeat TLI quantification is not consistent with a diagnosis of EPI (typically a TLI measurement at the low end of the reference interval), then an isolated pancreatic enzyme deficiency may be present.¹² In these cases, a trial of pancreatic enzyme supplementation is recommended, with a positive clinical response expected in dogs with isolated pancreatic enzyme deficiencies.

Concurrent pancreatitis or improper fasting may also increase TLI concentration and challenge the diagnosis of EPI.^13,14 Paired measurement of pancreatic lipase immunoreactivity and TLI can help to determine if pancreatitis could be confounding the diagnosis of EPI in an animal with a TLI concentration at the low end of the reference interval.

Repeat measurement of TLI is not beneficial in monitoring response to treatment. Rather, improvement or resolution of clinical signs exhibited at the time of diagnosis is used to determine control of EPI.

Traditionally, TLI is recommended to be measured on a fasting sample, as TLI concentrations may increase after eating; however, the magnitude of this increase is small and uncommonly affects clinical interpretation (~ 20%).^15-18 Therefore, while fasting is optimal, if an owner is unwilling to return to the clinic for a fasted blood draw, submitting a nonfasted sample is preferable to not performing the test. If a gray zone result is recorded on a nonfasted sample, then repeat measurement on a fasted sample should be considered.

Other Diagnostic Techniques

Given the diagnostic performance of the TLI assay, other diagnostic tests are rarely indicated and are usually only performed in geographic regions where the TLI assay is unavailable. Commercial canine enzyme-linked immunosorbent assays for quantification of fecal elastase may be a suitable alternative to TLI quantification when the TLI assay is unavailable. Low concentrations of fecal elastase are consistent with a diagnosis of EPI.¹⁹ Fecal proteolytic activity from 3 fecal samples can be considered as an alternative to TLI in cats with suspected EPI.²⁰

Treatment of EPI

Pancreatic Enzyme Replacement Therapy

All animals with EPI require pancreatic enzyme replacement therapy (PERT) to replace the missing digestive enzymes and enable normal digestion. There are 2 predominant approaches to replacing the deficient enzymes: feeding raw pancreas or utilizing commercial concentrated formulations of digestive enzymes.

Feeding fresh porcine pancreas is an inexpensive way to replace digestive enzymes; however, it is not routinely used due to inaccessibility and concerns about contamination related to the feeding of a raw product. Contamination of raw foods can create health risks for both the animal and the owner.²¹

Commercial concentrated digestive enzymes are readily accessible and are the author’s products of choice. Many different formulations exist, but no significant differences in efficacy have been noted between coated and noncoated enzyme formulations (as evaluated in dogs), suggesting that replacing the enzymes is more important than the specific formulation utilized.^22,23

For dogs, the author prescribes a dose of 1 teaspoon of enzymes per cup of food fed at each meal.¹⁰ Cats are started at 1 teaspoon of enzymes per meal.¹⁰ The enzymes can be mixed with the diet, and there is no need to preincubate the enzymes with the diet. Anecdotal evidence suggests that if an animal refuses to eat food to which enzymes have been added, the refusal could be due to a change in smell, which can be camouflaged via addition of other foods such as cheese or green tripe. If an inadequate response is noted, the dose can be titrated up to 2 teaspoons of enzymes per cup of food fed at each meal (dogs).¹⁰

Minimal adverse effects typically occur with PERT; however, bleeding gums have been reported,²⁴ as has anecdotal food intolerance, typically with pork-based formulations.

Despite no significant differences in efficacy between enzyme formulations in research studies, the author tries alternate enzyme formulations in refractory cases of EPI (e.g., pancrelipase [Creon]).

Once stool quality has returned to normal and the animal is gaining weight, treats can be added back into the feeding schedule if desired by the owner. Owners should be advised to monitor carefully for changes in stool consistency and other clinical signs of EPI when adding new items to their pet’s diet.

Dietary Modification

Highly digestible low-residue diets (often labeled as “GI diets”) are preferred over low-fat diets in the management of EPI, as low-fat diets tend to be calorie poor and can worsen malnutrition. Low-fat diets have not been shown to be associated with an improved outcome in dogs with EPI.²³ Significant fat restriction is rarely needed and should be reserved for dogs that have persistent steatorrhea despite optimized PERT and strict adherence to a highly digestible low-residue diet. Dietary fat should not be restricted in cats. During initial trials of these diets, treats should be withheld.

High-fiber diets should also be avoided as, like low-fat diets, they tend to be calorie poor, and excess fiber may interfere with the activity of digestive enzymes.²⁵ Selecting a lower-fiber diet may also allow for a reduced PERT dosage and thus reduce the cost of treatment.

In the author’s experience, incorrect diet selection is one of the most common causes of failure to regain body condition after diagnosis of EPI, and these cases are often inappropriately labeled as poorly responsive.

Cobalamin Supplementation

Serum cobalamin concentrations should be measured in all dogs and cats with EPI due to the high prevalence of vitamin B₁₂ deficiency in this population.^7,26 Low serum B₁₂ concentrations are an indicator of poorer prognosis in dogs with EPI, and supplementation of B₁₂ has been shown to improve response to therapy in cats with EPI.^7,23 Hypocobalaminemia results in part from deficiency of intrinsic factor, which is made by the pancreatic acinar cells and is needed for absorption of cobalamin.

The author supplements cobalamin in animals with a serum B₁₂ concentration of 400 ng/L or less, despite this being at the low-normal end of most reference intervals. Oral and subcutaneous cobalamin supplementation are equally effective in correcting B₁₂ deficiency.^27,28 If B₁₂ is initially within the normal reference interval, repeating the measurement in 3 months is recommended to ensure deficiency does not develop over time. If measurement of B₁₂ is not possible due to owner finances or other constraints, the author recommends empiric B₁₂ supplementation due to the high frequency of hypocobalaminemia and the limited adverse effect profile of the medication.

Evaluating Response to EPI Therapy and Troubleshooting Challenging Cases

A poorly responsive case of EPI demonstrates persistent clinical signs despite treatment. These cases are often frustrating for veterinarians, but a logical approach to identifying the underlying cause and treating it accordingly can improve clinical response.

First, it is reasonable to evaluate the validity of the original diagnosis. If the measured TLI concentration was low, the clinician can be confident in the diagnosis. However, if the original diagnosis was made based on an overall clinical assessment and response to enzyme supplementation, without TLI measurement, then TLI should be measured on a fasted sample. Pancreatic enzyme supplementation does not interfere with the results of the TLI assay.¹¹

Once the original diagnosis is validated, the clinician should consider the following potential differentials:

• Inadequate timeline to allow for clinical response
• Enzyme dose or formulation issue
• Inadequate diet
• Concurrent chronic enteropathy or other disease
• Persistent dysbiosis

Timeline

In some dogs, it takes up to 4 weeks for stool quality to improve on PERT and dietary manipulation, while it may take several months for body condition to improve.¹⁰ Therefore, if stool quality has improved but the animal has yet to gain significant weight in the first month or so of treatment, this may be normal and no additional adjustments may be needed. However, other causes of failure to gain weight should be considered, particularly in dogs with markedly poor body conditions.

Enzyme Dose and Formulation

During the initial treatment phase, PERT dose adjustment in response to clinical signs is appropriate; however, it is rare to need more than 2 teaspoons of high-quality PERT per cup of food fed.¹⁰ If higher doses are being considered, then an alternate enzyme formulation may be attempted and other potential causes of poor response to treatment for EPI should be investigated.

Diet Selection

As mentioned, inappropriate dietary selection may contribute to a lack of response to treatment. Most commonly, the chosen diet is low fat and too calorie poor to allow for weight gain and return to normal body condition. While fat is a challenging substance to digest, other components of the diet also contribute to digestibility, and highly digestible low-residue diets are preferred for their greater caloric density. Significant fat restriction is rarely needed and should be reserved for dogs that have persistent steatorrhea despite optimized PERT and adherence to a highly digestible low-residue diet. Dietary fat should not be restricted in cats.

Concurrent Disease

Animals that fail to respond to high-quality dose-titrated PERT and a highly digestible low-residue diet may have a concurrent chronic enteropathy or other disease that is contributing to clinical signs. Such enteropathies can be hard to detect, as many of the clinical signs and biochemical changes (e.g., hypocobalaminemia) are also expected in animals with EPI. It is the author’s opinion that refractory EPI cases should have a full abdominal ultrasound study performed to evaluate intestinal wall thickness, intestinal wall layering, and other abnormalities. If these are present, then intestinal biopsy should be recommended, provided no other explanation for poor response to EPI management is found. Concurrent disease is commonly seen in cats with EPI.

Dysbiosis

Dogs and cats may also have persistent changes in their intestinal microbiome (dysbiosis) despite treatment for EPI.^29-31 It is plausible that these changes could contribute to persistent clinical signs in these animals. Historically, antibiotics were trialed in poorly responsive EPI cases; these drugs may manipulate intestinal bacterial populations and could improve clinical signs in some dogs.³² Given concerns related to inappropriate antibiotic usage, the author prefers the use of prebiotics and probiotics in these cases to target any ongoing intestinal dysbiosis.

EPI Prognosis

The prognosis for EPI in both dogs and cats is generally good provided that high-quality PERT, a readily digestible diet, and cobalamin supplementation are provided. Lifelong therapy is typically needed, which can be costly. One way to reduce the ongoing cost of care is titrating PERT to the lowest effective dose. Reducing dietary fiber content may allow for further dose reduction in PERT. Concurrent disease (e.g., chronic enteropathy, cholangiohepatitis) may affect prognosis. Even with optimized medical therapy, some animals have persistent clinical signs. Additional research is needed to determine why this occurs.

Summary

EPI is an important diagnostic differential for dogs with poor stool quality and weight loss despite a good appetite. Unlike dogs, cats with EPI present with nonspecific signs, including weight loss alone. In both species, the diagnostic test of choice is the TLI test, with a low TLI concentration being consistent with EPI. Treatment consists of high-quality pancreatic enzyme replacement in conjunction with an easily digestible low-residue diet and cobalamin supplementation as needed. Most animals respond well to therapy. Suboptimal responses may be due to inadequate timeline to allow for a clinical response, an enzyme dose or formulation issue, an inadequate diet, concurrent chronic enteropathy, or persistent dysbiosis.