Exocrine pancreatic insufficiency in dogs and cats

Harry Cridge Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI

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David A. Williams Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL

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Patrick C. Barko Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL

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Abstract

Exocrine pancreatic insufficiency (EPI) is a malabsorptive syndrome caused by insufficient secretion of digestive enzymes from pancreatic acini. The most common causes of EPI in dogs and cats are pancreatic acinar atrophy and chronic pancreatitis. EPI is diagnosed by measurement of species-specific immunoassays for serum trypsin-like immunoreactivity, the concentration of which directly reflects the mass of functioning pancreatic acinar tissue. EPI is treated by pancreatic enzyme replacement therapy, nutritional management (low-residue diets with moderate fat content), and supplementation of cobalamin. Some dogs and cats have persistent clinical signs despite these treatments. Growing evidence suggests that these clinical signs may be due to enteric microbiota dysbiosis or the presence of concurrent diseases such as chronic enteropathies. Management of these abnormalities may improve outcome in dogs and cats with EPI. The long-term prognosis for dogs and cats with EPI is generally good if high-quality medical therapy is provided. Future studies are needed to further understand the causes of persistent dysbiosis in animals with EPI following initiation of pancreatic enzyme replacement therapy and assess the efficacy of treatments to ameliorate these abnormalities.

Abstract

Exocrine pancreatic insufficiency (EPI) is a malabsorptive syndrome caused by insufficient secretion of digestive enzymes from pancreatic acini. The most common causes of EPI in dogs and cats are pancreatic acinar atrophy and chronic pancreatitis. EPI is diagnosed by measurement of species-specific immunoassays for serum trypsin-like immunoreactivity, the concentration of which directly reflects the mass of functioning pancreatic acinar tissue. EPI is treated by pancreatic enzyme replacement therapy, nutritional management (low-residue diets with moderate fat content), and supplementation of cobalamin. Some dogs and cats have persistent clinical signs despite these treatments. Growing evidence suggests that these clinical signs may be due to enteric microbiota dysbiosis or the presence of concurrent diseases such as chronic enteropathies. Management of these abnormalities may improve outcome in dogs and cats with EPI. The long-term prognosis for dogs and cats with EPI is generally good if high-quality medical therapy is provided. Future studies are needed to further understand the causes of persistent dysbiosis in animals with EPI following initiation of pancreatic enzyme replacement therapy and assess the efficacy of treatments to ameliorate these abnormalities.

Introduction

Exocrine pancreatic insufficiency (EPI) is a malabsorptive syndrome caused by insufficient secretion of digestive enzymes from pancreatic acini. In 1856, the role of the exocrine pancreas in digestion and absorption of dietary lipids was recognized by Claude Bernard in experiments using dogs, cats, and rabbits.1 Improvement in protein and fat digestion in dogs fed raw porcine pancreas following total pancreatectomy constituted the first experimental evaluation of pancreatic enzyme replacement therapy (PERT) in 1890.2 Although dogs and cats have been important model species for research in pancreatic physiology, the first published report of spontaneous EPI in dogs was published in 1953 and in cats did not emerge until 1975.3,4 The diagnosis of EPI in dogs and cats has since been facilitated by the development of species-specific immunoassays for serum trypsinogen (trypsin-like immunoreactivity [TLI]), the concentration of which directly reflects the mass of functioning pancreatic acinar tissue. While EPI itself can be treated by PERT, managing associated cobalamin deficiencies and individualized nutritional approaches are usually required to achieve optimal clinical responses. Research suggests EPI is complicated by enteric microbiota dysbiosis (EMD), which the authors suspect to be a contributing factor to the persistence of clinical signs despite PERT.5,6 Although EPI is not as common as other chronic gastrointestinal disorders, it is an essential rule-out for dogs and cats with clinical signs of gastrointestinal dysfunction. The purpose of this narrative review is to provide a comprehensive and modern update on the diagnosis and management of EPI, incorporating information from published reports and the authors’ own experience diagnosing, treating, and investigating EPI in dogs and cats.

Epidemiology, Signalment, and Genetics

Exocrine pancreatic insufficiency has a worldwide distribution. The most well-documented breed predisposition is the German Shepherd Dog (GSD), and while any breed can be affected, Rough-coated Collies, Cavalier King Charles Spaniels, Cairn Terriers, Chows, Cocker Spaniels, Eurasier dogs, and West Highland White Terriers are reported to be at increased risk of EPI.712 Dogs and cats can develop EPI at any age, but the underlying etiology may affect the age of onset of clinical signs. Breeds affected by pancreatic acinar atrophy (PAA) are often affected at a younger age than those affected by EPI secondary to chronic pancreatitis (CP).11 Most cats are middle-aged to older at the time of diagnosis.13,14 Female dogs may be overrepresented, but this is not seen in all EPI studies.11,15 Males are slightly overrepresented in cases of feline EPI.13,14

The increased risk of EPI in certain breeds makes a heritable component likely, and many studies have investigated genetic markers of disease. Early studies of GSDs proposed an autosomal recessive inheritance pattern; however, test mating of 2 symptomatic GSDs failed to support this hypothesis.7,10,16 When these 2 dogs were bred, 4 of the 6 puppies had no clinical or pathological signs of EPI.16 All puppies would be anticipated to be affected if an autosomal recessive mode of inheritance existed. This study led to the suspicion of a polygenetic mode of inheritance and prompted additional studies in this area. Linkage analysis revealed no genomic regions linked (highest logarithm of odds, 2.5) with EPI.17 Genome-wide association studies in GSDs revealed several single nucleotide polymorphisms associated with PAA, many of which were located on chromosome 12.18 Three single nucleotide polymorphisms were located on the same locus, which maps to the dog leukocyte antigen (DLA).18 DLA-88 has been associated with EPI in GSDs.19 DLA-DQB1 alleles have also been associated with EPI in Pembroke Welsh Corgis.20 Other specific-candidate gene investigations based on data in rodent models, functional physiology, or genetic expression studies have failed to identify mutations associated with EPI. Additional research is needed in this area.

Pathogenesis, Pathophysiology, and Interactions with the Microbiome

Pathogenesis and pathophysiology

A variety of lesions can theoretically cause EPI in dogs and cats, including PAA, CP, pancreatic duct obstruction, and pancreatic neoplasia. In dogs, PAA is considered the most common cause of EPI. PAA is characterized by selective destruction of pancreatic acinar cells and their replacement with adipose and connective tissue in the absence of marked inflammation or fibrosis (Figure 1).21 As most dogs with PAA are diagnosed in the end stages of the disease process, the pathogenic factors initiating PAA are poorly understood. A previous investigation of dogs with early (subclinical) PAA identified lymphocytic pancreatitis and circulating autoantibodies against pancreatic acinar cells, suggesting an immune-mediated component to the disease.22 Chronic pancreatitis is reported to be the most common cause of EPI in cats; however, there is scant evidence to support this assertion. The authors have observed several cases in which pancreatic histopathology from cats with EPI revealed PAA in the absence of inflammation or fibrosis, and at least 1 such example has been reported in the literature.23 It is the authors’ collective clinical impression that PAA could be a major cause of EPI in cats, and we believe that the etiology of EPI in cats is worth reevaluating. Eurytrema procyonis (raccoon pancreatic fluke) has also been described as a potential cause of EPI in cats.24

Figure 1
Figure 1

Gross and microscopic images of pancreatic acinar atrophy in dogs. A—Gross image of the pancreas from a healthy dog. B—Microscopic (40X) image of the pancreas from a healthy dog. Pancreatic acini are shown next to the arrow, and the asterisk marks the location of an islet of Langerhans. C—Gross image of the pancreas of a dog with pancreatic acinar atrophy showing loss of pancreatic mass. D—Microscopic image (40X) from the pancreas of a dog with exocrine pancreatic insufficiency (EPI) with pancreatic acinar atrophy. The pancreatic acinar cells are replaced by adipose tissue (arrow) and with minimal inflammation or fibrosis.

Citation: Journal of the American Veterinary Medical Association 262, 2; 10.2460/javma.23.09.0505

Clinical signs associated with EPI are caused by defective digestion and absorption of dietary macromolecules (protein, fat, and starch).25,26 In health, the exocrine pancreas synthesizes and secretes proteases (trypsinogen, chymotrypsin, and elastase), lipase, and amylase into the proximal duodenum via the pancreatic duct. The exocrine pancreas has incredible functional redundancy, and, regardless of its underlying pathogenesis, clinical signs of EPI emerge once > 90% of pancreatic acinar cell mass is lost.27 The resulting deficit in the synthesis and secretion of pancreatic digestive enzymes leads to insufficient delivery of digestive enzymes into the lumen of the proximal duodenum. The resulting luminal enzyme deficiency prevents digestion of proteins, fat, and starch into their component monomers (amino acids, fatty acids, and mono- and disaccharides), which is required for their absorption by the intestinal epithelium. This malabsorptive state leads to nutritional deficiencies and calorie deficits. Malnutrition and the catabolic state resulting from a negative energy balance cause the considerable weight loss and polyphagia that are observed in many affected patients, especially dogs. The presence of undigested and unabsorbed macromolecules in the intestinal lumen causes osmotic diarrhea, which contributes to poor stool quality in dogs and cats with EPI.

Enteric microbiota dysbiosis

Another consequence of undigested nutrients in the gut lumen is that they become substrates for microbial fermentation. This is 1 factor predisposing to EMD, a state in which the composition of microbes in the gut lumen changes in ways that can promote gastrointestinal dysfunction. Disturbances in bacterial communities in the intestinal lumen have long been recognized in dogs with EPI. Early culture-based studies of duodenal fluid identified small intestinal bacterial overgrowth (SIBO) in dogs with EPI characterized by increased abundance of total obligate anaerobes, Lactobacillus, and Streptococcus.28,29 These differences in microbiota were associated with biochemical and structural changes in the duodenal mucosa, including decreased activities of brush border enzymes and villous atrophy.28,30 More recent investigations have utilized quantitative PCR and high-throughput nucleic acid sequencing of bacterial DNA in feces to characterize enteric microbial communities in dogs with EPI. These studies have revealed similar patterns of EMD characterized by decreased microbiota diversity; increased abundances of Escherichia coli, Lactobacillus, Bifidobacterium; and decreased abundances of Fusobacterium and Clostridium hiranonis.31,32 These dysbiotic changes in microbiota composition are associated with altered microbial metabolism, including decreased fecal concentrations of secondary bile acids and increased fecal concentrations of D-lactate.31 EMD can plausibly contribute to the pathophysiology of diarrhea, flatulence, and abdominal discomfort; changes in appetite; and other clinical signs in affected animals due to excessive gas production from anaerobic microbial metabolism, exacerbation of cobalamin deficiencies, and induction of intestinal mucosal inflammatory responses. To our knowledge, the gastrointestinal microbiomes of cats with EPI have not been studied. However, a recent untargeted metabolomics investigation identified disturbances in serum concentrations of microbial metabolites in the sera of cats with EPI, suggesting they have patterns of EMD similar to dogs.33

Diagnosis

Clinical presentation

Dogs with PAA may be asymptomatic (subclinical) at the time of diagnosis or may have more overt signs of EPI such as weight loss despite a good appetite, increased stool volume, steatorrhea, and flatulence.15,34 Other clinical signs may include poor coat quality, changes in behavior, and abdominal discomfort.34 Dogs with EPI secondary to CP may have a history of intermittent gastrointestinal upset and abdominal pain.35,36 Cats with EPI show fewer “classic” signs of EPI compared to dogs, with weight loss being the most commonly reported clinical sign across multiple studies.13,14,37 The lack of “classic” clinical signs means that these cases can be easily missed in clinical practice, unless the veterinarian actively screens for such cases. Other potential clinical signs include unformed feces, vomiting, anorexia, poor coat quality, and lethargy.13,14 Weakness and ataxia secondary to D-lactic acidosis have also been reported in a cat with EPI.38 Coagulopathies secondary to vitamin K deficiencies are also possible.39 Polyphagia appears uncommon in cats with EPI.13,14 Clinical signs of concurrent disease (eg, inflammatory chronic enteropathy [CE], cholangitis, diabetes mellitus, etc) may be present.

Routine blood work and diagnostic imaging findings

The results of a minimum database (CBC, serum chemistry, and urinalysis) are typically unremarkable in animals with uncomplicated EPI. Abnormalities that may be present typically reflect the presence of concurrent disease, which requires a separate diagnostic approach. Abdominal ultrasonography is commonly performed in dogs and cats with clinical signs consistent with EPI or small intestinal disease. Mean pancreatic thickness may be reduced, but EPI cannot be ruled out on the basis of a normal pancreatic ultrasonographic appearance or size.37,40 Another study,41 published in abstract form, noted no significant correlation between the size of the mid-right pancreatic limb and serum TLI concentration in cats. Other abnormalities that may be seen in cats include pancreatic duct dilation.37 Ultrasonographic evidence of concurrent intestinal changes is common.37,40

Trypsin-like immunoreactivity

Trypsin-like immunoreactivity measures serum trypsin and trypsinogen concentrations and is considered the test of choice for EPI. A radioimmunoassay was originally developed for use in dogs, and because these assays are species specific, an assay was subsequently developed for use in cats.42,43 These assays are unaffected by pancreatic enzyme supplementation. Serum TLI assays are highly sensitive for the diagnosis of EPI.44 Withholding food has historically been recommended before measurement of serum TLI, as concentrations of this biomarker have been shown to increase after feeding in both dogs and cats, but the magnitude of these changes rarely affects clinical interpretation of the result.4547 As methodologies have evolved, additional TLI assays have also been developed and each should be utilized with an appropriate reference interval, as the results of each assay may not be identical.48 Isolated selective pancreatic enzyme deficiencies (such as of pancreatic lipase) may result in low-normal TLI concentrations, but these animals would be expected to have a clinical response to pancreatic enzyme supplementation.49

Low serum concentrations of TLI are consistent with a diagnosis of EPI, and most laboratories also utilize a diagnostic gray zone in which repeat testing is recommended.50 While there is some evidence that there is a positive relationship between serum TLI concentrations and dietary protein percentage in dogs, the authors have observed that serum canine TLI concentrations remain within the reference interval even in extremely malnourished dogs.51 Increased TLI concentrations can be seen in animals with pancreatitis, which may complicate with diagnosis of EPI secondary to CP.52,53 Although serum trypsinogen is cleared by glomerular filtration, renal insufficiency has to be marked to lead to increased serum TLI concentrations.54 Measurement of pancreatic lipase immunoreactivity concurrent to TLI may assist in identification of concurrent pancreatitis.

Fecal elastase and other diagnostics

Prior to the advent and validation of the species-specific TLI assays, several methods were used to diagnose EPI, including gelatin film digestion tests, the N-benzoyl-L-tyrosyl-p-aminobenzoic acid test, fecal proteolytic activity, observation of lipid droplets and starch in feces, and fat absorption tests.44,5560 These methods were methodologically complex, unreliable, lacked specificity, or some combination thereof. Thus, these assays are no longer considered useful for diagnosing EPI and are not available to most veterinarians in practice. Currently, the only viable alternative to TLI for diagnosing EPI in dogs is a canine-specific patient-side ELISA for fecal pancreatic elastase 1 (cE1; ScheBo Biotech AG). This assay has been validated for canine feces, and concentrations > 20 μg/g exclude EPI whereas concentrations < 20 μg/g are consistent with EPI in dogs with compatible clinical signs.61 The fecal cE1 ELISA may be available in some developing countries where the TLI assay may be unavailable and is a viable diagnostic alternative in those circumstances. False positives are known to occur with the fecal cE1 ELISA, and healthy dogs from breeds predisposed to EPI (eg, GSDs and Rough-coated Collies) have lower fecal concentrations of cE1, which can overlap with those from dogs with EPI.61,62 Fecal proteolytic activity has been used in the diagnosis of EPI in cats; however, a minimum of at least 3 fecal samples must be collected to acquire reliable results.56,63 For these reasons, the TLI should still be considered the diagnostic test of choice for the diagnosis of EPI in cats and dogs.

Treatment

Pancreatic enzyme supplementation

Animals with EPI require PERT (Figure 2). Several different formulations of pancreatic enzymes exist, including enteric-coated and noncoated formulations in addition to raw pancreas. Enteric coatings are designed to protect the pancreatic enzymes as they pass through the stomach, but studies suggest no difference in efficacy between coated and noncoated preparations in dogs.64,65 Noncoated preparations are therefore often initiated as first-line therapy due to cost, but enteric-coated enzymes (eg, Creon) are considered by the authors in refractory cases when increasing doses of non–enteric-coated enzymes are ineffective. It is also important to note that enteric coatings are often formulated for the human gastrointestinal tract, and it cannot be assumed that their properties are well suited for use in dogs or cats. Potential adverse effects of PERT include oral bleeding.66 Dose reduction is recommended in these cases. Fresh raw pancreas contains digestive enzymes and may be fed to animals with EPI and may be inexpensive (when available). Porcine pancreas is commonly utilized and is effective. Raw products may be contaminated with bacterial pathogens and other infectious agents that could have negative impacts on the animal or their owner.67 They are used as a last resort by the authors of this review. Standard starting doses for PERT are guided by the manufacturer but typically start around 1 teaspoon/cup of food (or per 10 kg of body weight) for dogs per meal.68 If an inadequate clinical response is noted, the dose can be increased by half a teaspoon/cup of food, up to a maximum of 2 teaspoons of PERT/cup of food. It is the authors’ belief that doses > 2 teaspoons of high-quality pancreatic enzyme/cup of food are not necessary in the vast majority of cases. Other causes of poor treatment response should be investigated in these cases (see Troubleshooting Challenging Cases). Cats are often started at 1 teaspoon of PERT/meal/cat.69 Once an ideal body weight and good stool quality have been achieved, PERT can be dose decreased to the lowest effective dose (a one-fourth teaspoon/cup of food dose reduction every 2 weeks while monitoring body weight and stool quality). At this time, treats may be considered if so desired by the client, but careful monitoring for changes in stool consistency is needed. Any changes in stool consistency should result in discontinuation of treats. Most cases do not require additional PERT when treats are provided in moderation.

Figure 2
Figure 2

Responses to pancreatic enzyme replacement therapy (PERT) in dogs with EPI. A—A dog with EPI prior to the initiation of PERT. The subject has poor body condition (body condition score, 2/9) as evidenced by ribs, lumbar vertebrae, and pelvic bones that are easily visible without palpation. B—Feces from a dog with EPI prior to the initiation of PERT showing poor fecal quality and steatorrhea. C—The same dog with EPI following treatment of PERT showing improved body condition (body condition score, 4/9). The subject has gained a clinically important quantity of weight, and its ribs and other bony prominences are no longer visible. D—Feces from the same dog with EPI following treatment with PERT showing resolution of diarrhea and steatorrhea. Images used with permission of the dog’s owner and provided courtesy of Epi4Dogs Foundation Inc.

Citation: Journal of the American Veterinary Medical Association 262, 2; 10.2460/javma.23.09.0505

Dietary modification

Dietary fat and fiber content are important in the management of EPI. Historically, low-fat diets were recommended but can exacerbate malnutrition due to poor energy density, and they have not been associated with improved outcome.65 Low-fat diets may also worsen fat-soluble vitamin deficiencies and are generally avoided, unless refractory steatorrhea is present. Highly digestible, low-residue diets (often labeled as “gastrointestinal”) are often utilized by the authors, but dietary response appears to vary per animal.70 High-fiber diets are also generally avoided due to low energy density and concerns that fiber may interfere with lipase activity and nutrient assimilation.70,71 Diets low in insoluble fiber may also permit utilization of lower PERT doses, which may reduce the financial burden of the disease for some clients. Some dogs also appear to respond to hydrolyzed protein or novel antigen diets, prompting consideration of a concurrent CE (see Concurrent CE).

Cobalamin supplementation

Hypocobalaminemia is prevalent in dogs (> 60%) and cats (77% to 100%) with EPI.13,15,23 Hypocobalaminemia likely occurs as a result of increased uptake of cobalamin by the enteric bacteria and due to reduced concentrations of intrinsic factor, which is needed for cobalamin absorption.68 Hypocobalaminemia is an independent risk factor for decreased survival in dogs, and supplementation with cobalamin improves treatment outcome in cats.13,15 The authors recommend initiating cobalamin supplementation when serum cobalamin concentrations are < 300 ng/L in both dogs and cats. It is important to note that this value (< 300 ng/L) is within the low-normal end of the reference interval for several commercial cobalamin assays. Ideally, serum cobalamin concentrations would be monitored during therapy to determine whether supplementation was adequate to normalize serum cobalamin concentrations. Owing to the high prevalence of hypocobalaminemia and the presumed safety of cobalamin supplementation, the authors recommend supplementation in all patients with EPI for whom serum cobalamin cannot be measured. Both oral and parenteral cobalamin supplementations are effective at normalizing serum cobalamin concentrations (Figure 3).72,73

Figure 3
Figure 3

Strategies for cobalamin supplementation in dogs and cats with EPI. Recommendations for management of hypocobalaminemia in dogs and cats with EPI is synthesized from published reports and the authors’ experiences treating EPI. A—Proposed doses, routes of administration, and frequency of administration of cobalamin in dogs and cats. B—Algorithm for treating and monitoring cobalamin supplementation in dogs and cats with documented deficiencies.

Citation: Journal of the American Veterinary Medical Association 262, 2; 10.2460/javma.23.09.0505

Ancillary therapies

Acid-suppressant medications have been suggested to reduce gastric pH and improve the amount of intact enzyme that makes it through the stomach and into the small intestine. This is of particular importance for noncoated preparations and raw pancreas. Use of H2-receptor antagonists, however, has not been shown to improve outcome in dogs with EPI.65 Among owners of dogs with EPI, administration of digestive health supplements (eg, slippery elm extract) is common, but supportive evidence is lacking.

Troubleshooting Challenging Cases

Enzyme dose, formulation, and timeline to response

When considering a poorly responsive case of EPI, it is reasonable to begin with evaluation of PERT. As discussed above, most animals with EPI do not require doses of high-quality enzyme preparations > 2 teaspoons/cup of food. If higher doses than this are required, the authors recommend evaluating for other causes of poor response. Other potential causes include a poor-quality formulation, and thus a switch in enzyme preparation may be indicated. It is also noted that while many animals have improved stool consistency within a few days of PERT, it may take 2 to 4 weeks before optimal stool consistency is noted in some animals. Clinicians should therefore allow sufficient time before noting a failure to respond to PERT. Clinically important weight gain and restoration of body condition may take several months to improve. If weight loss is progressive in the face of a sufficient dose of a high-quality pancreatic enzyme supplement, concurrent CE should be considered and aggressively investigated.

Micronutrient deficiencies

Deficiencies in lipid-soluble vitamins are well described in humans with EPI.74,75 Dogs with EPI also have malabsorption of lipid-soluble vitamins that persists following initiation of PERT, and there is a case report of vitamin K deficiency in a cat with EPI.5,39 It is unclear how clinically important deficiencies in lipid-soluble vitamins are in dogs or cats with EPI. However, vitamins A, D, and E participate in regulating gastrointestinal health and it is plausible that deficiencies in lipid-soluble vitamins could contribute to clinical signs of gastrointestinal dysfunction that persist after PERT. In contrast with water-soluble vitamins (eg, cobalamin), toxic effects of hypervitaminosis from lipid-soluble vitamins are more common due to their ability to accumulate in bodily tissues of fluids. Supplementation with lipid-soluble vitamins should be instituted cautiously, ideally after consultation with a veterinary nutritionist and only after documenting a deficiency. Serial measurements of serum vitamin concentrations should be monitored to avoid overdosing.

Concurrent CE

The persistence of clinical signs of gastrointestinal dysfunction and EMD after PERT and positive responses to dietary therapies used to treat CEs raise suspicion that some dogs and cats with EPI may have a concurrent CE. A recent metabolomics investigation identified increased kynurenine, which is associated with inflammatory bowel disease in humans, in the sera of dogs with EPI.6 In retrospective studies, approximately 20% of cats with EPI have concurrent CE, including lymphoplasmacytic enteritis, and 5% have hypofolatemia consistent with CE affecting the proximal gut.13,23 Clinical signs of uncontrolled EPI and CE can be indistinguishable. The differential diagnosis of CE is beyond the scope of this review, but the authors recommend investigating for primary concurrent CE in dogs and cats with suboptimal response to PERT and for whom trials of other adjunct therapies have also failed.

Persistent dysbiosis

In many clinical cases, PERT is sufficient to ameliorate EMD and manage associated clinical signs. However, emerging evidence suggests that EMD can persist despite PERT in some animals. Studies of the fecal microbiome and fecal and serum metabolomes in dogs and cats with EPI have also identified persistent EMD and altered concentrations of microbial metabolites despite PERT.6,28,29,33 Thus, persistent EMD is a plausible explanation for persistent clinical signs in some dogs and cats with EPI following PERT. Treatments aimed at altering the enteric microbiome are therefore considered in dogs and cats with EPI.

Traditionally, antibiotics were among the most common adjunct therapies due to the presence of EMD/SIBO, although alternate approaches now include use of pre- or probiotics and potentially fecal microbiota transplantation. Evidence to support these therapies is limited. Probiotics and prebiotics are presumed to be well tolerated by the majority of patients. Thus, many clinicians will attempt trial therapy with pre- and probiotics before considering antibiotics. One small study76 revealed that tylosin ameliorated SIBO in dogs with EPI, but no controlled studies have reported the efficacy of antibiotics as an adjunct therapy for EPI. In light of scant evidence for their efficacy in EPI and emerging evidence that antibiotics can induce EMD, promote antibiotic resistance, and cause diarrhea in healthy dogs, the authors recommend antimicrobial therapy only after the enzyme dose/formulation and diet have been optimized (see above sections).7779 Tylosin is typically administered at 25 mg/kg once daily for 2 to 4 weeks in dogs. If a positive clinical response is observed (ie, improved stool quality), the dose can be tapered downward in 25% to 30% increments every 1 to 2 weeks to identify the lowest effective dose. If clinical signs return upon discontinuation, tylosin may be given indefinitely. The authors consider fecal microbiota transplantation for cases in which more traditional approaches have failed.

Prognosis and Conclusions

The prognosis for long-term management of dogs and cats with EPI with a high quality of life is generally good. A standard therapeutic strategy including PERT, cobalamin supplementation, and a high-quality diet is often all that is needed to restore normal body condition and fecal quality. Apparent spontaneous resolution of EPI has been noted but is extremely rare. Thus, the vast majority of dogs and cats with EPI require life-long PERT in addition to individualized adjunct therapies (diet, antibiotics, probiotics, prebiotics, etc). A retrospective study65 found that responses to PERT were complete in 60% of dogs, partial in 17%, and poor in 23%. Among dogs with incomplete responses to treatment, chronic diarrhea was the most common persistent clinical sign.65,80,81 The long-term prognosis for cats with EPI is considered good but often complicated by the presence of concurrent disorders including CE, CP, and cholangitis. Nonetheless, available evidence from retrospective studies suggests that 40% to 60% of cats have complete and 27% to 60% have partial responses to therapy.13,23

Conclusions and Future Directions

In conclusion, EPI should be considered a differential diagnosis for any dog or cat with clinical signs of gastrointestinal dysfunction, regardless of the age or breed. Serum TLI is the test of choice used to diagnose EPI, and species-specific assays are available for dogs and cats. The prognosis for EPI following initiation of PERT is good for both dogs and cats, but cobalamin supplementation and dietary modification are often necessary for an optimal response to therapy.

Acknowledgments

None reported.

Disclosures

The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.

Funding

The authors have nothing to disclose.

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  • Figure 1

    Gross and microscopic images of pancreatic acinar atrophy in dogs. A—Gross image of the pancreas from a healthy dog. B—Microscopic (40X) image of the pancreas from a healthy dog. Pancreatic acini are shown next to the arrow, and the asterisk marks the location of an islet of Langerhans. C—Gross image of the pancreas of a dog with pancreatic acinar atrophy showing loss of pancreatic mass. D—Microscopic image (40X) from the pancreas of a dog with exocrine pancreatic insufficiency (EPI) with pancreatic acinar atrophy. The pancreatic acinar cells are replaced by adipose tissue (arrow) and with minimal inflammation or fibrosis.

  • Figure 2

    Responses to pancreatic enzyme replacement therapy (PERT) in dogs with EPI. A—A dog with EPI prior to the initiation of PERT. The subject has poor body condition (body condition score, 2/9) as evidenced by ribs, lumbar vertebrae, and pelvic bones that are easily visible without palpation. B—Feces from a dog with EPI prior to the initiation of PERT showing poor fecal quality and steatorrhea. C—The same dog with EPI following treatment of PERT showing improved body condition (body condition score, 4/9). The subject has gained a clinically important quantity of weight, and its ribs and other bony prominences are no longer visible. D—Feces from the same dog with EPI following treatment with PERT showing resolution of diarrhea and steatorrhea. Images used with permission of the dog’s owner and provided courtesy of Epi4Dogs Foundation Inc.

  • Figure 3

    Strategies for cobalamin supplementation in dogs and cats with EPI. Recommendations for management of hypocobalaminemia in dogs and cats with EPI is synthesized from published reports and the authors’ experiences treating EPI. A—Proposed doses, routes of administration, and frequency of administration of cobalamin in dogs and cats. B—Algorithm for treating and monitoring cobalamin supplementation in dogs and cats with documented deficiencies.

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