Exocrine Pancreatic Insufficiency

The exocrine pancreas has an essential role in the digestion and absorption of nutrients. Pancreatic acini synthesize and secrete enzymes such as lipase, trypsin and amylase that digest fats, proteins and carbohydrates. Pancreatic duct cells secrete bicarbonate that maintains an optimal pH for digestive and absorptive processes, and intrinsic factor that enables the absorption of cobalamin (Vitamin B12). The exocrine pancreas also produces bacteriostatic peptides and defensins that regulate the upper GI flora, and has a role in maintenance of the intestinal mucosa and glucose homeostasis.

Dysfunction of the exocrine pancreas is broadly characterized by the loss of functional pancreatic mass (exocrine pancreatic insufficiency), or inflammation (pancreatitis), with consequent diarrhea and weight loss, or abdominal pain and vomiting respectively. This chapter will outline the role of nutrition in the pathogenesis and management of exocrine pancreatic disease in the dog.

Kenneth W. SIMPSON
BVM&S, PhD, MRCVS, Dipl ACVIM, Dipl ECVIM-CA

Dr. Simpson graduated from the University of Edinburgh (BVM&S) in 1984. His PhD (University of Leicester, 1988) focused on pancreatic and intestinal function in dogs, and was followed by clinical training at the University of Pennsylvania, and the Ohio State University. He is presently an Associate Professor of Medicine at Cornell University with clinical and research interests in internal medicine and gastroenterology.

1. Exocrine Pancreatic Insufficiency

Diagnosis

Overview

A diagnosis of exocrine pancreatic insufficiency (EPI) is made on the basis of compatible historical and clinical findings (Table 1), and by ruling out infectious, parasitic, metabolic, and anatomic causes of small bowel diarrhea and weight loss. The diagnosis is confirmed by demonstrating a subnormal serum concentration of trypsin-like immunoreactivity (TLI), recently reviewed by Westermarck & Wiberg(2003).

Signs

Dogs with EPI usually present for investigation of chronic diarrhea (feces of large volume and cow-pat consistency, often yellow to grey in color) (Figure 1) and weight loss (mild to extreme), which is often associated with a ravenous appetite. Pica and coprophagia are also common. A poor hair-coat (hair loss, eczema, dryness, scurf) polydipsia and marked muscle loss are observed in some dogs.

Figure 1. The feces of canine pancreatic insufficiency patients are often of large volume and cowpat consistency, and are discolored and highly pungent. (© M. Weber).

Polyuria and polydipsia may be present when exocrine pancreatic insufficiency caused by chronic pancreatitis is complicated by diabetes mellitus. Acute abdomen due to mesenteric torsion has also been associated with EPI.

Supplementary Tests

Clinicopathological Tests

Routine hematology and biochemistry are fairly unremarkable in dogs with EPI. Modest increases in alanine amino-transferase (ALT) and a decrease in cholesterol are observed in some dogs. Pan-hypoproteinemia is not a feature of EPI, and its presence suggests that primary small intestinal disease is causing the diarrhea and weight loss, rather than EPI.

The presence of hyperglycemia and glucosuria in dogs with signs of EPI should prompt consideration of diabetes mellitus secondary to chronic pancreatitis, or pancreatic hypoplasia.

Serum concentrations of cobalamin (Vitamin B12) and Vitamins A and E can also be markedly reduced in dogs with EPI. In contrast, serum folate concentration is often increased. Serum concentrations of zinc and copper are decreased in dogs with experimental pancreatic insufficiency, whereas serum iron and transferrin saturation are increased.

Specific Diagnosis

The specific diagnosis of EPI is made by demonstrating a subnormal concentration of trypsin-like immunoreactivity (TLI) in a fasted serum sample (Williams & Batt, 1988). Serum TLI is considered to originate solely from the pancreas and is an indicator of pancreatic mass and inflammation (Simpson et al., 1991).

In dogs with EPI caused by atrophy or chronic inflammation the amount of TLI leaking from the pancreas into the circulation is reduced, and a subnormal TLI concentration can be demonstrated (Figure 2).

Figure 2. Interpretation of tyrosin-like immunoreactivity (TLI) values in fasting dogs.  

Patients with persistently intermediate TLI concentrations are likely to have partial EPI that may progress to complete EPI (Wiberg et al., 1999a; Wiberg & Westermarck, 2002).

The TLI test is a simple and reliable way of confirming a diagnosis of EPI. However, if the TLI test result does not fit the patient's clinical signs it is prudent to rerun the test after ensuring an overnight fast to rule out sampling/handling/technician error. The TLI test will not detect conditions that may cause the intra-luminal destruction of pancreatic enzymes e.g., hyperacidic states such as gastrinoma and mast cell tumor, but these conditions have other diagnostic features such as hematemesis and esophagitis to distinguish then from primary EPI.

Diagnostic Pitfalls

EPI must be distinguished from primary intestinal disease.

The combination of diarrhea, weight loss, ravenous appetite, and relatively normal laboratory findings, often in a breed that is predisposed (e.g., German Shepherd) (Figure 3 & Figure 4), strongly suggests EPI is a likely cause.
Figure 3. Frequency distribution of age at diagnosis of canine exocrine pancreatic insufficiency in 199 german shepherd dogs and 102 dogs of other breeds.

Figure 4. Frequency distribution of breeds for 301 cases of canine pancreatic insufficiency.

The presence of large bowel diarrhea, frequent vomiting, pallor, jaundice, edema or ascites should prompt consideration of other more likely diagnoses. Hypoproteinemia is not a feature of uncomplicated EPI and usually indicates a protein losing enteropathy.

Do not rely solely on the TLI test result without other supportive evidence of exocrine pancreatic disease.

Decision Tree

The differential diagnosis of EPI includes other causes of small bowel diarrhea and weight loss (Table 2).

Epidemiology

Risk Factors

Pancreatic acinar atrophy (PAA) is probably the most common cause of exocrine pancreatic insufficiency (EPI) in the dog (Figure 3). Dogs under five years of age diagnosed with EPI are usually suspected of having pancreatic acinar atrophy, whereas older dogs likely have a higher incidence of pancreatitis induced degeneration (Hall et al., 1991). Dogs with chronic relapsing pancreatitis are considered at increased risk of developing EPI.

Breed Predispositions

Many different breeds have been diagnosed with EPI (Figure 4).

A familial predisposition to pancreatic acinar atrophy has been reported in German Shepherd Dogs, Collies and English Setters (Westermarck, 1980; Boari et al., 1994; Moeller et al., 2002; Wiberg, 2004). As it is impossible to determine the cause of atrophy in an end stage pancreas, prospective studies of the development of canine PAA have been conducted. These longitudinal studies have identified German Shepherd dogs and Rough Coated Collies with sub-clinical exocrine pancreatic insufficiency, detected by assay of circulating TLI, in whom pancreatic atrophy is preceded by a marked lymphocytic infiltration (Westermarck et al., 1993a; Wiberg et al., 1999b, 2000). This strongly suggests an autoimmune basis for PAA. There is no evidence that a lack of trophic factors e.g., CCK, or anti-pancreatic antibodies play a role in the genesis of PAA.

Breeds such as Miniature Schnauzers appear to be overrepresented with relapsing pancreatitis and may be predisposed to EPI.

Pathophysiological Mechanisms of EPI

Exocrine pancreatic insufficiency (EPI) in the dog is most often a consequence of a severe reduction of pancreatic mass caused by pancreatic acinar atrophy, or chronic pancreatitis (Figure 5a-Figure 5c).

Figure 5a. Photographs of EPI due to pancratic acinar and chronic atrophy and chronic pancreatitis. Chronic pancreatitis. Fibrosis and atrophy are evident in this section from the pancreas of a dog with EPI secondary to pancreatitis (x10; H&E coloration).  

Figure 5b. Photographs of EPI due to pancratic acinar and chronic atrophy and chronic pancreatitis. Lymphocytic inflammation precedes the development of EPI in dogs with familial acinar atrophy (x40; H&E coloration).

Figure 5c. Photographs of EPI due to pancratic acinar and chronic atrophy and chronic pancreatitis. Islet cells, stained for insulin (brown), and surrounded by a sea of atrophied exocrine tissue are relatively normal in dogs with EPI. (Glucose tolerance is abnormal but responds to enzyme supplementation - see text for details) (x20; immunocoloration for insulin).  

Pancreatic hypoplasia with concomitant EPI and diabetes mellitus has been rarely documented. In theory, EPI can also occur secondary to:

• The increased destruction, or decreased activity, of pancreatic enzymes in patients with acid hypersecretion
• Decreased synthesis and secretion of enzymes in the presence of severe malnutrition.

Extensive loss of exocrine pancreatic mass (approx. 90%), whether by atrophy or chronic inflammation is required before signs of EPI are evident (Simpson et al., 1992). The predominant clinical signs of EPI, diarrhea, weight loss and a ravenous appetite can be directly attributed to decreased intra-duodenal concentrations of pancreatic enzymes, bicarbonate, and various other factors with resultant malassimilation of fats, carbohydrates and proteins (Figure 6).

Figure 6. Pathophysiology of exocrine pancreatic insufficiency.  

Malabsorption of fat soluble vitamins and cobalamin, and changes in the number and composition of the small intestinal bacterial flora have also been documented in dogs with EPI and may contribute to their clinical condition (Williams et al., 1987; Westermarck et al., 1993b; Adamama-Moraitou et al., 2002). Subnormal serum concentrations of cobalamin are frequently documented (approximately 75% of cases) in dogs with EPI and are likely a consequence of intrinsic factor deficiency, disrupted binding of cobalamin to IF (by intestinal pH, lack of proteases) and bacterial consumption of cobalamin (Figure 7) (Batt et al., 1989; Simpson et al., 1989a; Simpson et al., 1993).

Following ingestion, cobalamin is released from food in the stomach (Figure 7). It is then bound to a non-specific cobalamin-binding protein of salivary and gastric origin called haptocorrin. Intrinsic factor (IF), a cobalamin binding protein that promotes cobalamin absorption in the ileum, is produced by the stomach and pancreas in dogs. The affinity of cobalamin for haptocorrin is higher at acid pH than for IF, so most is bound to haptocorrin in the stomach.

Upon entering the duodenum haptocorrin is degraded by pancreatic proteases, and cobalaminis transferred from haptocorrin to IF, a process facilitated by the high affinity of IF for cobalamin at neutral pH. Cobalamin-IF complexes traverse the intestine until they bind to specific receptors (previously called IFCR, but recently dubbed cubilin) located in the microvillus pits of the apical brush-border membrane of ileal enterocytes.

Cobalamin is then transcytosed to the portal bloodstream and binds to a protein called transcobalamin 2 (TC II), which mediates cobalamin absorption by target cells. A portion of cobalamin taken up by hepatocytes is rapidly (within an hour in the dog) re-excreted in bilebound to haptocorrin.

Cobalamin of hepatobiliary origin, in common with dietary derived cobalamin, under goes transfer to IF and receptor mediated absorption, thus establishing enterohepatic recirculation of the vitamin.

Low serum cobalamin concentrations in dogs have been associated with exocrine pancreatic insufficiency (EPI), severe intestinal disease, IF-Cbl receptor abnormalities, and conditions associated with the proliferation of enteric abacteria e.g stagnant loops.

Figure 7. Cobalamin absorption in the dog.  

Other abnormalities encountered in dogs with EPI include alterations in:

• Glucose homeostasis (subclinical glucose intolerance) (Rogers et al., 1983)
• Pancreatic and gastrointestinal regulatory peptides (e.g., vasoactive intestinal polypeptide, gastric inhibitory polypeptide, somatostatin, pancreatic polypeptide) (Hellmann et al., 1991)
• The regulation of small intestinal mucosal growth, enzyme synthesis and enzyme degradation (Batt et al., 1979; Sorensen et al., 1988; Simpson et al., 1989b).

Trace element status in EPI has received relatively little study. One report of German Shepherd dogs with EPI indicates normal serum concentrations of copper and zinc. However, it has been recently demonstrated that serum copper and zinc decline, and serum iron and transferrin saturation increase, after pancreatic duct ligation (Adamama-Moraitou et al., 2001).

The clinical significance of these abnormalities is unclear. The severe malassimilation of nutrients in EPI can lead to protein calorie malnutrition (view EPI Case Study) that may further compromise residual pancreatic function, intestinal absorption and metabolic homeostasis.

Dermatological abnormalities are variably present in German Shepherd dogs with EPI and their presence may be related to protein calorie malnutrition, deficiencies in trace elements and minerals and potentially adverse reactions to food.

EPI Case Study - Neutered Female Boxer Age 7 Years

Treatment

Enzyme Supplement

A non-enteric enzyme preparation must be given at mealtimes in situations of insufficient enzyme secretion by the exocrine pancreas. Only powder enzyme preparations coated to resist the gastric acid should be administered. The alternative is feeding fresh pancreas.

Use only non-enteric coated powdered supplements that are in date and stored appropriately (dog: 0.25 - 0.4 g/kg body weight/meal or 2 tsp/20 kg body wt/meal) (Westermarck et al., 1987; Wiberg et al., 1998). The enzyme supplement should be mixed into the food. Pre-incubation does not significantly impact outcome (Pidgeon & Strombeck, 1982). A new batch, change of preparation or increased amounts may produce a response. If cessation of diarrhea and weight gain are observed over a two week period the animal is maintained on this regimen and an attempt is made to decrease the enzyme supplement to the lowest effective dose.

If the therapy fails, the lot or the mode of presentation may be changed, or the enzyme quantities increased. If a response is not being achieved with a dose of 0.4 g/kg of non-enteric coated powdered extract or 3 g/kg body weight/meal whole pancreas, inadequate enzyme replacement is an unlikely reason for treatment failure.

Micronutrients

Fat soluble vitamins are likely candidates for malabsorption, and low levels of Vitamins A and E have been reported in German Shepherd dogs with EPI. Vitamin E can be given orally (400500 IU SID q 1 month). It seems prudent to examine the vitamin K status of dogs with EPI who have laboratory evidence of a coagulopathy.

Cobalamin deficiency can have a myriad of effects on the body and the provision of supplementary parenteral cobalamin (cyanocobalamin, vitamin B12) is recommended because pancreatic enzyme supplementation does not reverse the deficiency. Studies in dogs indicate that the parenteral administration of a single dose of cyanocobalamin (250 - 500 µg SQ once per month) is enough to prevent recurrence of metabolic abnormalities for up to one month. The cobalamin malabsorption does not resolve after enzyme supplementation and lifelong therapy is recommended.

Figure 9. Role of vitamin B12 in the organism. Vitamin B12 plays a fundamental role in protein synthesis and red blood cell production and has an enzyme function in many essential biochemical reactions.  

Feeding Dogs with EPI

The pivotal role of the exocrine pancreas in the digestion and assimilation of nutrients would suggest that EPI is a disease that would be particularly amenable to nutritional intervention. In theory a highly digestible, fat restricted diet (fat is considered the most difficult nutrient to assimilate and lipase activity is the limiting step in its digestion) that is low in fiber (fiber is indigestible, lowers energy density and hinders pancreatic enzyme activity) would seem justified in dogs with EPI. However, analysis of the outcome (survival) of 116 dogs with EPI indicates that dogs that received a modified diet (n=73, 30% dead) did not outlive those receiving a standard diet (n=43, 35% dead) (Hall et al., 1991).

A 50% reduction of the initial dose is possible in the majority of the dogs (Simpson et al., 1994). This adaptation of the dose is important, because the cost of pancreatic enzymes is an obstacle to treatment for many owners, who prefer to euthanize their dogs.

Potential Advantages of a High Fat Content

In complete contrast to the paradigm of fat restriction in EPI, diets with 43% calories from fat have been shown to promote better protein, fat and carbohydrate digestibility compared to diets containing 18 and 27% calories from fat in dogs with experimental EPI (Suzuki et al., 1999). Improved preservation of exogenous pancreatic enzymes, especially lipase, could explain this observation. It is of note that studies in dogs with experimental exocrine pancreatic insufficiency demonstrated that fecal fat output is more dependant on the digestibility of the fat, rather than the amount fed (Pidgeon, 1982; Pidgeon & Strombeck, 1982).

A case report of 3 German Shepherd dogs with EPI and poor haircoat demonstrated that a 19% fat DM (40.8 % of calories from fat), soy protein isolate hydrolysate and rice diet was well tolerated and improved fecal quality, haircoat and weight gain (2 - 10 kg) compared with the dogs previous diets. The dogs recovered optimal body condition within a 2-month period (Biourge & Fontaine, 2004).

These observations suggest that high fat, highly digestible diets are not contra-indicated in the management of EPI. Traditionally, dietary supplementation with medium chain triglyceride oil (24 mL/meal) has been considered a beneficial way of providing calories to severely malnourished patients fed a highly digestible fat restricted diet but supportive data are lacking. However feeding a higher fat and thus more energy dense diet could promote a rapid restoration of optimal body weight without recourse to medium chain triglyceride oil.

As the importance of nutritional modification in the management of EPI is far from clear, and the costs associated with special diets are a common reason for euthanasia this author recommends initially feeding a good quality maintenance dog food (i.e., high digestibility) with an appropriate exogenous enzyme supplement mixed into it. If the response to treatment is poor then dietary modification is an option (see treatment failure - below).

Treatment Failures

Inadequate Enzyme Supplementation

This is probably the number one cause of treatment failure. Some dogs develop an aversion to the enzyme supplement and raw pancreas may have to be used, if attempts to disguise the powder are unsuccessful. Stomatitis has been reported as a side effect of exogenous enzyme supplementation and may be remedied by decreasing the supplement by 50% (Rutz et al., 2002). Decreasing the enzyme supplement may also be considered in the majority of dogs with EPI.

Bacterial Overgrowth/intolerance

EPI may impact the quantity and composition of the small intestinal flora and compromise the host response to a normal or abnormal flora. These alterations are usually addressed by treatment with an enzyme supplement. However, in some patients, diarrhea cannot be eliminated until antibiotics are administered. In these patients treatment failure may reflect decreased synthesis of intestinal mucosal enzymes associated with EPI. The presence of an abnormal flora cannot be predicted accurately by measuring serum concentrations of cobalamin and folate, so a trial with an antibiotic such as oxytetracycline (20 mg/kg PO TID 28d), or tylosin (10 mg/kg PO TID) can be undertaken.

Benefits of dietary modification in dogs (n=14) fed a "moderate fat, highly digestible low fiber diet" for four weeks versus a maintenance diet were restricted to a tendency (8/14 dogs) to reduced borborygmi, flatulence and fecal volume (Westermarck et al, 1990). A study in 21 EPI dogs, evaluating the benefit of feeding a low fat (13% of calories), low fiber diet compared to the usual commercial or home cooked diet failed to show any significant benefit of severe fat restriction (Westermarck et al., 1995).

Finally, feeding a low fat (13% of calories) diet in combination with exogenous enzymes (2.5 g/300 g food) to dogs (n=20) has been shown to promote a 24% average weight gain over a four month period, and a good response in 17/20 dogs (Simpson et al., 1994). However, the role of the diet in this study is unclear as 11/20 dogs were subsequently successfully maintained on a variety of diets after the trial period.

Small Intestinal Disease

Routine hematology and biochemistry are almost always normal in uncomplicated EPI, so abnormalities such as hypoproteinemia (which may indicate a protein losing enteropathy) should be pursued.

Dietary Modifications

Once these common reasons for treatment failure (inadequate enzyme supplementation, the presence of bacterial overgrowth or intolerance, and concomitant small intestinal disease) have been addressed, nutritional modification must be considered.

Dietary management of small intestinal disease is typically based on feeding a highly digestible, usually a rice based diet that is restricted in fat. If dietary sensitivity is suspected an antigen restricted or protein hydrolysate diet may be employed. Hydrolysates are produced by enzymatic proteolysis of native proteins which results in an array of peptides that are small enough so that they may not be recognized by, nor trigger a reaction by the immune system (Guilford, 1996). These peptides are also highly digestible, therefore reducing their retention time in the lumen of the intestine. Soy hydrolysates have been used extensively in the prevention of food sensitivity in babies and in calves (Lallès et al., 1995; Terracciano et al., 2002). If gastrointestinal signs resolve after the dietary trial (usually one to two weeks) it is necessary to rechallenge the individual with the original diet to confirm a diagnosis of dietary intolerance. The addition of specific antigens such as beef, soy, chicken to the diet that induced remission is required to document hypersensitivity.

It is of interest that the use of a soy hydrolysate diet with relatively high fat content was effective in facilitating weight gain, decreasing diarrhea and improving haircoat in three dogs with EPI that had failed to respond to diet and pancreatic extracts (Biourge & Fontaine, 2004) (Figure 10).

Figure 10. German sherpherd suffering from exocrine pancreatic insufficiency.

If response to treatment is still poor then acid suppression to protect pancreatic enzymes and empirical dietary modifications can be made, while carefully reviewing the diagnosis of EPI and considering other underlying disorders.

Dogs with confirmed EPI that respond poorly to appropriate enzyme supplementation and antimicrobial therapy usually require investigation of the small intestine.

Conclusion/prognosis

In a majority of dogs suffering from EPI a high quality maintenance diet supplemented with powdered pancreatic enzymes resolves most of the abnormalities associated with the disease. The relatively high cost of enzyme supplementation and special diets can significantly impact the outcome, precipitating euthanasia. If pancreatitis or diabetes is associated, prognosis is more reserved.