Exocrine pancreatic insufficiency (Proceedings)

Etiology and Pathogenesis

Exocrine pancreatic insufficiency (EPI) is a syndrome, which is caused by insufficient synthesis and secretion of digestive enzymes by the exocrine portion of the pancreas, leading to insufficient activity of digestive enzymes in the lumen of the small intestine. Pancreatic acinar atrophy is the most common cause of EPI in the dog, followed by chronic pancreatitis. In contrast, chronic pancreatitis is the most common cause of EPI in cats and humans. Other, less common causes of EPI in dogs and cats are pancreatic or extrapancreatic masses that lead to an obstruction of the pancreatic duct. Congenital pancreatic hypo- or aplasia, as well as deficiencies of individual pancreatic digestive enzymes or of enteropeptidase have not been reported in dogs and cats, but likely do occur sporadically.

In human beings it has been shown that the exocrine pancreas has a remarkable functional reserve. Ninety percent of its functional reserve must be lost before clinical signs of EPI develop. Digestive enzymes of pancreatic acinar origin play an integral role in the assimilation of all major components of food stuff and a lack of pancreatic digestive enzymes leads to malassimilation in two ways. First and foremost, the digestive tract is inefficient in breaking down macromolecules when pancreatic digestive enzymes are lacking. In addition, intestinal mucosal transport mechanisms for mono- and disaccharides, amino acids, and fatty acids are also disturbed. The cause of this malabsorption is unknown, but it is speculated by some to be due to a lack of trophic factors, normally secreted by the exocrine pancreas. The nutrients remaining in the intestinal lumen lead to loose voluminous stools and steatorrhea. At the same time, a lack of nutrients causes weight loss and may lead to vitamin deficiencies in some cases. Serum cobalamin (vitamin B12) concentrations are undetectable or markedly decreased in almost all cats and a more than 80% of dogs with EPI. Serum folate concentrations in dogs with EPI are often increased suggesting the presence of complicating small intestinal bacterial overgrowth. In contrast, serum folate concentrations in cats with EPI are often decreased, indicating concurrent small intestinal disease. Secondary vitamin K responsive coagulopathy is rare in dogs and cats with EPI but has been reported and should be tested for if a bleeding tendency is present.

In patients with EPI caused by chronic pancreatitis, destruction of pancreatic tissue may not be limited to the acinar cells and concurrent diabetes mellitus (DM) may be observed. In most human patients with chronic pancreatitis, both exocrine and endocrine functional reserve are ultimately lost. However, overt DM usually appears later in the disease process than does malassimilation. At this point it is unknown whether dogs and cats with chronic pancreatitis follow the same pattern of progression, but it is intriguing to speculate whether EPI may be common, but often undiagnosed in those dogs and cats with DM that are difficult to regulate.

Clinical Picture and Diagnosis

Dogs with EPI due to PAA are most often young adult German Shepherd dogs, but dogs and cats with EPI due to other causes are usually middle-aged to older and can be of any breed. Clinical signs most commonly reported in dogs and cats with EPI are polyphagia, weight loss, and loose stools or diarrhea. Vomiting and anorexia are observed in some patients with EPI and may indicate the presence of a concurrent condition, such as inflammatory bowel disease, rather than a primary clinical sign of EPI. All of the clinical signs observed in patients with EPI are non-specific and are also seen in other disorders more commonly seen in middle aged to older dogs and cats. Some common conditions causing polyphagia in middle-aged to older small animals are hyperthyroidism in cats, corticosteroid treatment in both dogs and cats, and diabetes mellitus also in both dogs and cats. Common differential diagnoses for dogs and cats presenting with weight loss are hyperthyroidism in cats and dental disorders, chronic renal failure, heart failure, neoplasia, and chronic intestinal disorders, such as inflammatory bowel disease in both dogs and cats. Finally, the most common disorders causing diarrhea in middle aged to older dogs and cats are chronic intestinal disease, such as inflammatory bowel disease and chronic renal failure.

The feces from small animal patients with EPI are most commonly pale, loose, voluminous, and may be quite malodorous. In rare instances these patients may also develop watery diarrhea. The high fat content of the feces can lead to a greasy appearance of the hair coat, especially in the perianal and tail region of cats.

Results from routine blood tests are within the normal range in most cases. In a few cases lymphopenia, lymphocytosis, neutrophilia, eosinophilia, and elevations of hepatic enzymes have been reported. Also, abdominal radiography or ultrasonography do not show any specific changes in these patients. Several tests have been recommended to estimate exocrine pancreatic function in dogs and cats. The bentiromide absorption test, commonly known as PABA test, plasma turbidity test, microscopic examination of feces for undigested fat, starch, or muscle fibers, and fecal proteolytic activity (FPA), all have been recommended for the diagnosis of EPI. With the exception of FPA, all of these tests are rather unreliable or impractical and are therefore not recommended. Fecal proteolytic activity can be determined by either azocasein- or azoalbumin- based methods, or by a radial enzyme diffusion method, but at least three stool samples from consecutive days should be evaluated and feces should be frozen immediately and shipped on ice in order to prevent loss of FPA in the samples, making this test not very practical. Currently, evaluation of FPA is only recommended in species for which a serum TLI assay is not available.

Immunoassays for the measurement of serum trypsin-like immunoreactivity (TLI) in dogs and cats have been developed and validated. These tests are highly specific for EPI in both dogs and cats. Dogs with a serum cTLI of ≤ 2.5 µg/L and cats with a serum fTLI ≤ 8.0 µg/L can be diagnosed with EPI, respectively. A recent report has shown that some German Shepherd dogs have subclinical EPI with severely decreased serum cTLI concentrations. These dogs have a lack of exocrine pancreatic tissue at biopsy, but no or only intermittent clinical signs of EPI. This highlights the remarkable functional reserve of the exocrine pancreas and the entire gastrointestinal tract in dogs.

Recently, a new assay for measurement of fecal elastase in dogs has been developed and validated. Unfortunately, some normal dogs or dogs with chronic small intestinal disease may have a decreased fecal elastase concentration. Because of the low incidence of dogs with EPI a few false positive results of the assay lead to an overall large number of false positive dogs (low positive predictive value) making this test unreliable.

Another new diagnostic test for the assessment of exocrine pancreatic function, pancreatic lipase immunoreactivity has been developed and validated for use in dogs and cats. While serum PLI concentration is highly specific for exocrine pancreatic function there is some minimal degree of overlap of serum cPLI concentrations between healthy dogs and dogs with EPI. Therefore, serum cTLI and fTLI concentrations remain the diagnostic tests of choice for dogs and cats with exocrine pancreatic insufficiency, respectively.

Treatment

Most dogs and cats with EPI can be successfully treated by dietary supplementation with pancreatic enzymes. Dried extracts of bovine or porcine pancreas are available (e.g. Viokase® or Pancrezyme®). The clinical impression in dogs and cats that powder is more effective than tablets, capsules, and especially enteric-coated products has also been substantiated in human patients with EPI. Initially, one teaspoon per 10 kg body weight and meal should be given in dogs and one teaspoon per cat and meal in cats. Oral bleeding has recently been reported in 3 of 25 dogs with EPI treated with pancreatic enzyme supplements. The oral bleeding stopped in all 3 dogs after the dose of pancreatic enzymes was decreased. Moistening the food pancreatic/powder mix also appears to decrease the frequency of this side effect.

If the owner has access to fresh pancreas this may be a viable alternative to use of pancreatic powder. However, there is a slight risk of transmission of Aujeszky's disease from raw pork pancreas, BSE from raw bovine pancreas, and Echinococcus from raw game pancreas. One to three ounces (30-90 g) of raw chopped pancreas can replace one teaspoon of pancreatic extract. Raw bovine pancreas can be kept frozen for several months without loss of enzymatic activity. Preincubation of the food with pancreatic enzymes, supplementation with bile salts, or concurrent antacid therapy are unnecessary in most canine and feline patients with EPI. When clinical signs have resolved the amount of pancreatic enzymes given can be gradually decreased to the lowest effective dose, which may vary from patient to patient, and from batch to batch of the pancreatic supplement.

Even though pancreatic enzyme supplementation causes the clinical signs to subside in almost all patients, it has been shown in human beings and dogs with EPI that nutrient absorption, and particularly fat absorption are not normalized by enzyme supplementation. This is thought to be due to the low pH in the stomach leading to irreversible damage of the pancreatic lipase contained in the supplement. Even though gastric pH can be raised by administration of antacids, the negative effect of the increased intraluminal gastric pH on fat digestion by gastric lipase appears to cancel much of the positive effect, so that overall there is only a minimal increase in fat absorption, which is clinically not important in most patients. However, the use of omeprazole has recently been shown to be efficacious in human patients with EPI and may be tried if the patient does not respond to routine therapy. Some authors have suggested feeding low fat diets in order to accommodate impaired fat digestion. However, this may even further decrease fat assimilation and may potentially lead to serious complications associated with hypovitaminoses of fat-soluble vitamins and conditions associated with a lack of essential fatty acids. Some types of dietary fiber interfere with pancreatic enzyme activity. Therefore, a diet low in insoluble or non-fermentable fiber should be fed.

Response to enzyme supplementation alone may not be satisfactory in some canine or feline patients with EPI. This is not surprising if one considers that many dogs and especially cats with EPI also have a serious depletion of total body cobalamin stores. Serum cobalamin and folate concentrations should be routinely evaluated in small animals with suspected EPI, and dogs and cats with severely decreased serum cobalamin concentrations should be treated with cobalamin parenterally. Even though hypovitaminoses of other vitamins, especially vitamin K, are not very common, they have been reported in some cats with EPI and should be anticipated as potential complications.

Some dogs and cats do not respond to enzyme supplementation and cobalamin application. These patients likely have concurrent small intestinal disease. In dogs with EPI small intestinal bacterial overgrowth is common and may need to be treated with antibiotic therapy. In cats with EPI, inflammatory bowel disease can occur concurrently.

Prognosis

EPI is associated with an irreversible loss of pancreatic acinar tissue in most cases, and complete recovery is therefore extremely rare. However, with appropriate management and monitoring these patients usually gain weight quickly, pass normal stools, and can go on to live a normal life for a normal life span.