exocrine PANCREATIC INSUFFICIENCY

EPI is characterized by a lack of effective pancre­atic exocrine secretions in the small intestine. It is most often a consequence of the severe reduction in pancreatic mass caused by pancreatic acinar atrophy, or chronic pancreatitis, but may occur sec­ondary to excessive secretion of gastric acid (increased destruction and decreased activity of pancreatic enzymes by acid) or severe protein mal­nutrition (decreased synthesis of pancreatic enzymes).

Pancreatic acinar atrophy (PAA) is probably the most common cause of EPI in the dog, whereas chronic pancre­atitis is the most common cause in the cat. The precise cause of PAA has not yet been determined (Box 10-2). A familial predisposition to PAA has been reported in German shepherd dogs, collies, and English setters. Histologically, canine PAA closely resembles the pancreas of CBA/J mice in which ultrastructural and biochemical studies suggested that pancreatic atrophy was a consequence of the premature activation of trypsinogen and chy­motrypsinogen within the zymogen granule. However, it is impossible to determine the cause of atrophy in a pancreas with end-stage disease, so prospective studies of the development of canine PAA have been conducted. The initial study demonstrated that subcellular pancreatic abnor­malities (characterized by fusion of zymogen gran­ules and proliferation of endoplasmic reticulum) and a decrease in TLI preceded the development of gross pancreatic atrophy, reduced pancreatic protease secretion, and diarrhea in one dog. However, a subsequent investigation in dogs with subclinical EPI, detected by assay of circulating TLI, has shown that atrophy is preceded by a marked lymphocytic infiltration, suggesting an autoimmune basis for the disease. Studies that have examined the possibility that decreased CCK release or antipancreatic antibodies play a role in the genesis of PAA have yielded no evidence to support their involvement in the development of PAA.

Pathophysiology

The extensive loss of exocrine pancreatic mass (approximately 90%), whether by atrophy or chronic inflammation, is required before signs of EPI are evi­dent. The major signs of EPI are diarrhea, weight loss, and an ensuing ravenous appetite. These signs can be attributed to decreased intraduodenal con­centrations of pancreatic enzymes, bicarbonate, and various other factors with resultant malassimilation of fats, carbohydrates, and proteins. Abnormalities in levels of fat-soluble vitamins and cobalamin have been documented in dogs and cats with EPI and may contribute to their clinical condition. Increased sus­ceptibility of the enterocyte to damage by bacteria or their products and potentially an increase in small intestinal flora have been observed in dogs with EPI. Other abnormalities encountered in dogs with EPI include alterations in glucose homeostasis (sub- clinical glucose intolerance), pancreatic and GI regu­latory peptides (e.g., vasoactive intestinal polypeptide, gastric inhibitory polypeptide), and the regulation of small intestinal mucosal growth, enzyme synthesis, and enzyme degradation. The clinical significance of these abnormalities is unclear. The marked maldigestion of nutrients in EPI may lead to the development of protein-calorie malnutrition, which can further compromise residual pancreatic function, intestinal absorption, and metabolic homeostasis.

Diagnosis

A diagnosis of EPI is usually made on the basis of compatible historical and clinical findings and by ruling out infectious, parasitic, metabolic, and ana­tomic causes of small bowel diarrhea and demon­strating a subnormal circulating concentration of TLI (species-specific TLI: less than 2.5 μg∕L in dogs, less than 8 μg∕L in cats).

Clinical Findings

Dogs and cats with EPI usually have a history of chronic small bowel diarrhea (large volume, cow­pat consistency) and weight loss (mild to extreme), which is often associated with a ravenous appetite.

Clinicopathologic Tests

Results of routine hematologic and biochemical studies are usually unremarkable in cats with EPI. Modest increases in ALT concentration and a decrease in cholesterol concentration are observed in some dogs. Serum concentrations of cobalamin are usually subnormal in both dogs and cats with EPI. Serum concentrations of folate may be high in dogs with EPI. Serum folate concentrations are decreased in some cats as a consequence of con- commitant inflammatory bowel disease or intes­tinal lymphoma. Serum concentrations of vitamin E are often markedly reduced in dogs with EPI. Vitamin K—sensitive coagulopathies have been reported in cats with EPI. The presence of hyper­glycemia and glucosuria should prompt considera­tion of diabetes mellitus secondary to chronic pancreatitis or pancreatic hypoplasia.

Tests of pancreatic Function or Mass

The analysis of feces for proteolytic activity (film digestion, azocaesin assay) and the indirect estima­tion of intestinal chymotrypsin activity (BT-PABA test) for the diagnosis of EPI have been largely superseded by the development of an assay that determines the concentration of TLI in serum. Serum TLI is considered to be derived solely from the pancreas and can be used as an indicator of pancreatic mass or inflammation. In dogs and cats with EPI caused by atrophy or chronic inflam­mation, the amount of TLI that leaks from the pan­creas into the circulation is reduced and a subnormal TLI concentration can be demonstrated. Healthy dogs usually have a fasting (overnight fast) TLI con­centration greater than 5.0 μg∕L, whereas dogs with EPI caused by reduced pancreatic mass have fasting concentrations less than 2.5 μg∕L.

The BT-PABA test and fecal azocaesin digest test are likely to be the best means of diagnosing EPI that is secondary to the destruction of pancreatic enzymes by hypersecretion of gastric acid.

Treatment

Exogenous Pancreatic Enzymes

Powdered pancreatic extracts (dog: 0.12 to 0.2 g∕lb body weight per meal or 2 tsp∕45-lb body weight per meal or 2.5 g∕300-g food; cat: 1 tsp per meal two times a day) are far superior to enteric-coated tablets, granules, and capsules. Preincubating enzymes with food is not advantageous. Raw chopped pan­creas (dog: 0.7 to 1.4 g∕lb body weight per meal; cat: 30 to 90 g per meal two times a day) is an effective treatment when available and can be stored frozen for at least 3 months. In patients that show a good response the dose of pancreatic extract or pancreas can be gradually decreased to the smallest amount that maintains remission.

Diet

In clinical practice a good response has been observed when patients with EPI are fed either a normal maintenance diet or a highly digestible fat- restricted diet that is supplemented with pancre­atic enzymes. The outcome in terms of survival of dogs with EPI is reported to be similar in dogs with EPI fed maintenance diets and those fed modified diets.

Highly digestible fat-restricted diets are theo­retically attractive due to the limited digestive capabilities of patients with EPI. Clinical studies in dogs have shown highly digestible diets to be ben­eficial in reducing fecal volume, borborygmi, and flatulence but have no clear effects on fecal consis­tency, appetite, or coprophagy.

Vitamin Supplementation

Cobalamin deficiency can have a myriad of effects on the body, so the provision of supplementary cobalamin (cyanocobalamin, vitamin B_n) is pru­dent. It has recently emerged that dogs and cats do not have the capacity to store large quantities of cobalamin in their bodies and can become rapidly depleted when normal homeostasis is disrupted by EPI or intestinal disease. Studies in dogs indicate that the parenteral administration of a single dose of cyanocobalamin (1 mg subcutaneously) is enough to prevent recurrence of metabolic abnormalities for up to 1 month. Cats may require supplementation every 2 weeks to maintain normal serum concentra­tions of cobalamin. Dogs with EPI may also have to be supplemented with Vitamin E (400 to 500 IU orally once a day for 1 month). A vitamin K—responsive coagulopathy has been reported in cats with EPI, and it seems sensible to examine the vita­min K status of dogs with EPI that have laboratory evidence of a coagulopathy.

Treatment Failures

Confirm EPI

Review the patient's history, physical examination, and laboratory findings to ensure that EPI is a likely cause of the diarrhea. If the TLI test results do not fit the patient, then resubmit the test and/or evaluate pancreatic function by measuring fecal proteolytic activity.

Inadequate Enzyme Supplementation Ensure that the enzyme supplement being admin­istered is appropriate (non—enteric-coated pow­der), current, and being fed at the correct dose. A new batch, change of preparation, or increased amounts may produce a response. In dogs if a response is not being achieved with a dose of 0.2 g/lb of non—enteric-coated powdered extract or 1.4 g/lb body weight per meal whole pancreas, consider other reasons for treatment failure. Some dogs and cats develop aversions to the enzyme supplement, and raw pancreas may have to be used if attempts to disguise the taste are unsuccessful. Rarely some dogs develop a stomatitis related to the enzyme supplement.

Hyperacidity

Lipase is the most acid-sensitive enzyme, and its activity may be enhanced by decreasing gastric acid secretion. In dogs a treatment trial with ci­metidine (2.5 to 5 mg/lb orally two times a day) may reveal whether the enzyme supplement is being inactivated. This problem has not been studied in cats with EPI.

Antibiotic-Responsive Diarrhea∕"Bacterial Overgrowth”

Small intestinal bacterial overgrowth has been diagnosed in dogs with EPI when a cut-off value greater than 5 (log 10 colony-forming units [CFUs] per milliliter) of duodenal juice is applied. The bacterial flora of dogs with EPI created by pancreatic duct ligation increases after the induc­tion of EPI but returns towards baseline after sup­plementation with pancreatic enzymes. These observations suggest that increases in bacterial numbers in EPI are a consequence of increased substrate availability secondary to EPI. The bacte­rial counts in this experimental study (6.4 [log 10 CFUs per milliliter]) were within the range for healthy dogs, and antimicrobials were not needed to control clinical signs. Most dogs with sponta­neous EPI respond to treatment with enzyme sup­plementation and do not require antibiotics. However, some dogs need and respond to antibi­otic therapy. In those dogs it is likely that the bal­ance between intestinal damage and repair is altered by EPI: increased degradation of microvil­lar enzymes by the increased (relatively) bacterial flora versus decreased degradation by pancreatic enzymes in the face of decreased synthesis of microvillar enzymes.

The abnormal flora cannot be predicted accu­rately by serum concentrations of cobalamin and folate, so a trial with an antibiotic such as oxy­tetracycline (9 mg/lb orally two times a day for 28 days) may be undertaken in dogs that are unre­sponsive to enzyme and dietary manipulation. Antibiotic-responsive diarrhea has not been reported in cats with EPI.

Small Intestinal Disease

Some dogs and cats with EPI have small intestinal disease causing malabsorption despite adequate enzyme supplementation. Results of routine hema­tologic and biochemical studies are almost always normal in uncomplicated EPI, so abnormalities such as hypoproteinemia (which may indicate a protein-losing enteropathy) should be pursued. Dogs and cats with EPI that respond poorly to the above treatment modifications and have no evi­dence of extraintestinal disorders usually require further investigation of the small intestine. Further evaluation that should be considered includes checking the serum folate level, ultrasound, and endoscopy with intestinal biopsy.

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