Feline exocrine pancreatic insufficiency

Introduction

Exocrine pancreatic insufficiency (EPI) results from inadequate production of enzymes from the pancreatic acinar cells, leading to maldigestion, malabsorption and subsequent clinical signs, such as weight loss and diarrhea. Although EPI has previously been considered rare in the cat, it is now recognized that many cases escaped diagnosis in the past due to the lack of sensitive and specific diagnostic tests, low awareness for the disease, and its co-existence with other gastrointestinal (GI) conditions that cause similar clinical signs. Until recently, the literature on feline EPI was sparse, consisting of reports of confirmed or suspected EPI in 10 individual cats published between 1975 and 2009 1,2,3,4,5,6,7,8,9, as well as two small case series that together encompassed a total of 36 affected cats 10,11. More recently, a large retrospective study that evaluated 150 cats with EPI has been published 12, and in 2021 a small multicenter retrospective study described the ultrasonographic and clinicopathologic findings in 22 cats with EPI 13.

Epidemiology

The true prevalence of feline EPI is unknown, and (as noted above) the condition has traditionally been regarded as being rare in the cat, with only a few published case reports. However, since the introduction of the feline trypsin-like immunoreactivity (fTLI) test in 1995 14, considerably more cases have been diagnosed. In a recent study, the Gastrointestinal Laboratory’s database at Texas A&M University was searched over an approximately 2-year period (2008-2010), and 1,094 of 46,529 serum samples (2.4%) from cats submitted for fTLI measurement had levels consistent with a diagnosis of EPI 12. Despite the fact that the population used in this study is skewed (because it reviewed cats that had GI signs and therefore a possible suspicion of EPI), it appears that EPI is a condition that is not uncommon in cats. It is uncertain if these figures reflect a true increase in prevalence, or are merely an indication that clinicians now have a greater awareness of the disease and better means for arriving at a diagnosis. Therefore, although its true prevalence is yet to be determined, EPI should be suspected in cases with a compatible clinical picture.

Etiology and pathophysiology

No studies have specifically investigated the potential causes of feline EPI, although chronic pancreatitis leading to gradual and extensive destruction of the acinar cells has almost always been traditionally cited as the sole etiology. However, this idea was based on a small number of case reports 13,15, and although chronic pancreatitis is still believed to be the most common cause of feline EPI, other etiologies may also exist. Although not proven, the belief is that a prolonged time period is necessary for chronic inflammation to cause almost complete destruction of the exocrine pancreas; however, recent studies have noted that young cats can develop EPI, making chronic pancreatitis a less likely cause, especially in this age group 12. Other potential etiologies for EPI could include pancreatic acinar atrophy (reported in a small number of cases), Eurytrema procyonis infestation (a fluke found in parts of the USA, and again reported in a small number of cases), pancreatic hypoplasia or aplasia, and pressure atrophy due to pancreatic duct obstruction 1,2,3,4,5,6,7,8,9, 13. Whilst isolated pancreatic lipase deficiency has recently been reported as a cause of canine EPI (with other pancreatic enzymes remaining within normal parameters) 16, this has not yet been reported in cats.

The exocrine pancreas is thought to have exceptional functional reserve, and clinical signs of EPI are believed to develop only when > 90% of the secretory capacity is lost 13. Regardless of the cause, insufficient production and secretion of pancreatic enzymes into the small intestine leads to maldigestion of nutrients. The large amount of undigested nutrients in the intestine may lead to osmotic diarrhea, while decreased absorption of nutrients causes weight loss.

Of major importance is the pathophysiologic association between pancreatic function and cobalamin absorption. A cobalamin-binding protein, intrinsic factor, facilitates cobalamin absorption in the ileum, but in contrast to dogs, where intrinsic factor is also produced in the stomach, in cats it is produced exclusively in the exocrine pancreas. EPI therefore leads to reduced production and secretion of intrinsic factor, resulting in decreased intestinal absorption of cobalamin, and hence hypocobalaminemia and cobalamin deficiency 17.

Where EPI is a result of chronic pancreatitis, destruction of the endocrine portion of the pancreas may lead to concurrent diabetes mellitus. Additionally, many cats with EPI may have concurrent pancreatic inflammation, a chronic enteropathy (typically inflammatory bowel disease and/or GI small cell lymphoma) and/or hepatic disease.

Signalment and clinical signs

There is no significant breed or sex predisposition for EPI 12; most affected cats are middle-aged or older, but the reported age range is from 3 months to 19 years 12. This underlines the fact that EPI should be considered in cats of any age.

The clinical signs of affected cats are nonspecific and are the same as those seen with many other more commonly diagnosed conditions (e.g., hyperthyroidism, chronic enteropathies, pancreatitis, chronic kidney disease). Weight loss is by far the most common clinical sign (Figure 1) and was present in more than 90% of 150 cats in one study, and was the only clinical sign in 5% of the cases 12. Loose stools occurred in 62% of the cats, with 2/3 of them having occasional watery diarrhea (Figures 2 and 3). This is in contrast with the typical EPI dog, where loose stools are reported in most cases (e.g., 95% in one study 18). Other clinical signs include poor haircoat (50%), polyphagia (42%), anorexia (42%), lethargy (40%), vomiting (19%), and a greasy haircoat 12. Some of the reported signs (e.g., anorexia, depression, vomiting) are not typical of EPI and are likely associated with concurrent diseases (e.g., chronic enteropathy, or inflammation of the liver and/or pancreas) than EPI per se. There is one report of a cat with EPI that developed D-lactic acidosis (presumably due to increased intestinal fermentation as a result of bacterial overgrowth) which presented with clinical signs of weakness, lethargy and ataxia 8, but this is considered to be rare.

It is clear that the clinical presentation of many cats with EPI differs from and is more confusing than the typical presentation seen in dogs. Clinical signs are more subtle and less specific in cats, and signs from comorbidities are more common. Therefore, EPI should be suspected in cases with unexplained weight loss or anorexia, even when diarrhea or polyphagia are not present, or when vomiting or depression is the main presenting sign and where weight loss might be less noticeable.

Diagnosis

Exocrine pancreatic insufficiency will be initially suspected based on clinical presentation, but because various feline GI diseases can produce signs that overlap with those of EPI (and will often occur concurrently with EPI), every cat with a chronic GI disease or signs should ideally be tested for EPI. Cats with conditions such as IBD or GI small cell lymphoma that do not respond to appropriate treatment may have concurrent undiagnosed EPI. Therefore, any cat diagnosed with a chronic enteropathy or other GI problem that continues to lose weight or have loose stools despite appropriate treatment should have EPI included in the differential diagnosis list (Figure 4).

Cats with EPI usually have normal or non-specific changes on complete blood count and serum biochemical profile, but again concurrent disease can result in various abnormalities (e.g., anemia, increased liver enzymes, hyperglycemia, hypoalbuminemia), but none of these are specific for EPI. Serum cobalamin concentrations are decreased in most cats with EPI (80-100%) 12, but there is evidence that tissue cobalamin is depleted before hypocobalaminemia develops, and so even normocobalaminemic cats could still have cellular cobalamin deficiency 17. Although a common finding in cats with EPI, hypocobalaminemia is not specific for the condition, because it often occurs with other conditions such as IBD, GI lymphoma, and hyperthyroidism 17.

EPI is a functional disease that requires a definitive functional diagnosis 13. The gold standard is measurement of serum feline trypsin like immunoreactivity (fTLI) concentration (ideally performed on a fasting sample); this has 85-100% specificity, and although the sensitivity is unknown, it is considered to be high 10,12,13. TLI assays are species-specific, and therefore the tests developed and validated for dogs or humans are inappropriate for use in cats. fTLI assay measures the serum levels of trypsinogen produced by the exocrine pancreas, and the only validated assay currently available is provided by the Gastrointestinal Laboratory at Texas A&M University. In EPI, due to significant reduction in the functional capacity of the exocrine pancreas, subnormal serum fTLI concentrations are seen; the reference interval is 12-82 μg/L, and values ≤ 8 μg/L are considered diagnostic for EPI. Some cats with clinical GI signs have fTLI concentrations in the intermediate range (8-12 μg/L), and these cases should be retested a few weeks or months later to check whether values have normalized or have dropped into the diagnostic range for EPI. Because trypsinogen is excreted by the kidney, serum fTLI concentrations may be falsely raised in cats with decreased kidney function 19, which can hamper the diagnosis. In azotemic cats where EPI is suspected, re-evaluation of serum fTLI concentrations after improvement of the azotemia may be necessary.

Imaging modalities (radiography, ultrasound, computed tomography) are unhelpful for the diagnosis of EPI because they do not reflect the functional capacity of the pancreas. However, imaging can be useful for the diagnosis or exclusion of concurrent diseases, or conditions that can mimic EPI. In a recent multicenter study, it was shown that EPI causes minimal to no ultrasonographic changes in cats, although thin pancreatic parenchyma and pancreatic duct dilation were noted in some cases, which may raise the suspicion of EPI 13. Similarly, histopathology samples, or even a small pancreas noted on gross examination, are not indicative for a diagnosis of EPI, again because they do not reflect the functional capacity of the pancreas, although EPI may be suspected based on compatible findings.

Treatment

Enzyme replacement therapy

As in dogs, the mainstay of treatment in cats with EPI is pancreatic enzyme supplementation. There are several commercial products (dried extracts of porcine pancreas) available, but no studies have objectively evaluated the efficacy of the different products and preparations in cats. No difference was identified with regards to the specific product or type of pancreatic enzyme used for treatment of feline EPI in one study, and therefore all products may be equally effective 12. Although older reports supported the use of powdered products in dogs (with enteric-coated products being considered less effective), a recent prospective, placebo-controlled study showed that enteric-coated products may actually be more efficacious 20. Although raw pancreas from beef, pork, or game may also be used 13, these may contain potentially dangerous pathogens, and the author’s preference is powdered or enteric-coated products.

Regardless of the product used, pancreatic enzymes should be administered with each meal. Enteric-coated products are ideally given immediately after a meal, while powdered products should be mixed thoroughly with food; preincubation with food does not appear to be necessary. Dosage is empirical, although initially 5 mL (1 teaspoon) of enzyme powder per meal is commonly used 13, and enteric-coated products can be started at 300 mg of pancreatin per day (divided in each meal); however, it is necessary to titrate the selected option for each cat based on response to treatment. This is expected to be quick, with resolution of loose stools usually seen within the first week, and once the clinical signs disappear a gradual reduction to the lowest effective dose should be attempted.

If raw pancreas is used, about 50 g per meal is appropriate as an initial dose, with subsequent adjustments as needed. Portions of raw pancreas can be kept frozen until use for several months without loss of efficacy, but owners must be aware that this option may be associated with a small risk of infectious and parasitic disease transmission (e.g., bovine spongiform encephalitis, Aujeszky’s disease, and parasites such as Echinococcus spp.) 13.

Due to their ability to break down protein and fat, pancreatic enzymes can cause irritation and ulcers if they have prolonged contact with the oral or esophageal mucosa. Therefore, powdered pancreatic enzymes should be mixed thoroughly with food, while administration of tablets or capsules should be followed by some food and water consumption to reduce the risk for stomatitis and esophagitis 13.

Cobalamin supplementation

Cobalamin supplementation is also of major importance and has been shown to favorably affect treatment response in both EPI cats and cats with chronic enteropathies, two conditions that often co-exist 12,21. Cobalamin deficiency can lead to intestinal inflammation and villus atrophy, disturbance of various biochemical pathways, and malabsorption of nutrients such as folate 17. In cats with GI disease and severe hypocobalaminemia, cobalamin supplementation led to significant increases in bodyweight and a lessening of vomiting and diarrhea 21. In a study of 150 cats with EPI, cobalamin supplementation favorably affected the response to treatment, even in cats with normal serum cobalamin concentrations 12. Finally, hypocobalaminemia associated with certain GI diseases in dogs has been shown to be a negative prognostic factor, and hypocobalaminemia in dogs with EPI is associated with shorter survival times 22,23.

The exact serum cobalamin concentration that indicates cellular cobalamin deficiency and a need for supplementation is currently unknown – hampered by the fact that normal serum cobalamin ranges vary greatly between laboratories. The use of markers of cobalamin deficiency – such as serum methylmalonic acid (MMA) – is more useful but not routinely available 24.

Whilst cats with hypocobalaminemia clearly require supplementation, some normocobalaminemic cats with EPI (especially those in the lower end of the reference range) may also benefit from a supplement, possibly because they have cellular cobalamin deficiency 12,17,24. Because virtually all cats with EPI either have or are prone to develop cobalamin deficiency due to lack of intrinsic factor, it might be recommended that all cases should be given a supplement, regardless of their serum cobalamin concentration.

Due to lack of intrinsic factor and the resulting impaired cobalamin absorption by the GI tract, parenteral cobalamin supplementation is typically recommended 13,17. Studies on the kinetics of parenteral cobalamin supplementation in cats with or without GI disease indicate that the serum half-life of cobalamin is 5 and 13 days respectively 25. Although protocols for supplementation have been published, the efficacy may be variable depending upon the underlying GI disease, the frequency of administration, and the formulation used 13,17, and no studies have specifically evaluated cobalamin supplementation protocols in cats with EPI. The author currently recommends either hydroxocobalamin (preferably) or cyanocobalamin at a total dose of 250 μg (500 μg for cats weighing > 5 kg) per cat, given either SC or IM every 2 weeks for 6-8 weeks. After this period cobalamin is administered at monthly intervals, with serum cobalamin re-evaluated every 3 months, and many cats will require long-term supplementation despite enzyme replacement treatment for EPI.

Recent evidence indicates that oral supplementation may be just as effective as parenteral administration for correcting cobalamin deficiency in cats with GI disease, but no studies have specifically evaluated the efficacy of this option in cats with EPI. Therefore, the author currently recommends parenteral cobalamin administration for all cats with EPI. If this is not possible, 250 μg of cobalamin per cat (either using a specific oral cobalamin preparation or the same injectable cobalamin preparations described above) may be given daily for 2-3 months, with subsequent re-evaluation of serum cobalamin concentrations.

Antibiotics and intestinal microbiota modification

Antibiotics have been used in some dogs as part of EPI treatment, supposedly to control concurrent intestinal dysbiosis, although no clear benefit for this practice has been established. Antibiotic use was not found to affect treatment response in cats with EPI in one study 12, and since disturbances of the microbiota in feline EPI have not been fully described or confirmed, antibiotic use is of unknown benefit in these cases. Given that the above study did not show antibiotics had a positive effect on treatment response, and because they have been shown to cause long-term dysbiosis and antimicrobial resistance, the author currently does not recommend antibiotics for cats with EPI. In cases which do not respond to enzyme and cobalamin supplementation, further diagnostic investigation is required, as these cats may have concurrent small intestinal disease and antibiotic use is unlikely to improve the outcome. If antibiotic treatment is deemed necessary, a trial with metronidazole (15 mg/kg q12h PO) or tylosin (20 mg/kg, q12h PO) may be attempted, but this should be reserved as a last option.

Multi-strain, high-dose probiotics may be able to control intestinal dysbiosis and could be used if this is suspected, but again no studies are available. Finally, fecal microbiota transplantation (FMT) is gaining ground as a means of intestinal microbiota modification (and likely the most effective one) but studies in cats with EPI are lacking. FMT may also be attempted in cases where intestinal dysbiosis is suspected.

Dietary recommendations

No studies have evaluated the effect of different diets on the outcome of cats with EPI, but a good quality, high protein maintenance diet would seem appropriate in most cases, unless concurrent diseases are present that dictate the use of a specific clinical diet. Hypoallergenic or elimination diets are commonly used in cats with chronic enteropathies and these would also seem appropriate in cats with EPI, especially because of the likelihood of concurrent GI disease. In the past, low-fat diets have been recommended for the management of EPI (especially in dogs), but again no studies exist in cats.

Other treatments

Some clinicians recommend using a proton-pump inhibitor (e.g., omeprazole or pantoprazole) concurrently with pancreatic enzyme replacement therapy to reduce gastric acidity and decrease enzyme inhibition in the stomach. However, the benefits of such treatment are unknown, and most cats seem to respond well without such intervention. However, it may be worthwhile giving a proton pump inhibitor to a cat that has not responded well to pancreatic enzyme and cobalamin supplementation to see if this improves matters.

Finally, there have been occasional reports of cats with EPI that presented with a coagulopathy that has responded to vitamin K supplementation 5. Although believed to be very rare, if a bleeding condition is noted in an EPI cat, coagulation parameters should be measured, and vitamin K supplementation initiated if appropriate.

Prognosis

Overall, response to treatment is considered good in 60% of cats with EPI, and most cases that are treated appropriately typically have an excellent prognosis and a good quality of life 12. Only 13% of reported cases have had a poor response to treatment 12; the reasons for this are not clear. Lack of or partial response to treatment might be due to a lack of cobalamin administration, or the presence of inadequately managed concurrent diseases as previously mentioned. All cats that do not respond to appropriate treatment should be reevaluated for other possible diagnoses or significant concurrent disease.

Conclusion

Exocrine pancreatic insufficiency (EPI) in cats is likely more common than recognized in clinical practice, but is often missed because of non-specific clinical signs and limited availability of appropriate tests. Ideally, all cats with a chronic enteropathy, and especially those that do not respond to initial treatment, should be tested for EPI by measurement of feline-specific TLI. Cats with undiagnosed and untreated EPI as a concurrent component of other chronic GI conditions will likely have an inadequate response to treatment, while most cats diagnosed with EPI will have a good response to appropriate therapy.