Exocrine pancreatic insufficiency (EPI) is a relatively frequent disorder in the dog, while it is rare in the cat. EPI is a malabsorption disorder characterized by an insufficient secretion of pancreatic enzymes. The inadequate production of digestive enzymes, or a deficiency in their secretion, causes the accumulation of non-digested substances within the intestinal lumen, which have an osmotic effect and provide a culture medium for the microbial flora. This condition, together with the resulting complications, is the cause of severe intestinal inflammation, which is associated with clinical signs. EPI is especially present in some breeds: principally in the German Shepherd and Collie, but also in the Labrador, Setter and Dobermann. The pancreas is an organ with a considerable reserve capacity; the clinical signs are therefore present only when at least 90% of its secretory capacity is compromised.
ETIOLOGY AND PATHOPHYSIOLOGY
Pancreatic acinar atrophy (PAA) is the most important cause of EPI in the dog. Although signalled in many breeds, this condition is typical of the German Shepherd, Scottish Shepherd and of the Eurasian/Eurasier. EPI has always been considered an autosomal recessive hereditary disorder. In order to study its hereditary pattern, some recent studies1,2 have used microsatellite markers to scan the genome, with the goal of identifying the causal recessive autosomal gene; the results have however been inconclusive. A study specifically targeted on the German Shepherd breed has also reported negative results. An English study4 on the association between breed and EPI confirmed the greater incidence of the disorder in breeds such as the German Shepherd, Collie and Cavalier King Charles Spaniel, and has furthermore identified a predisposition also in the Chow Chow. This study also highlighted a lower incidence of EPI in breeds traditionally considered at risk, such as the Boxer, Labrador, Golden Retriever and Rottweiler. A recent article3 identified 12 cases of combined exocrine and endocrine pancreatic insufficiency in a period of 15 years in young Greyhound breed animals, with histological alterations of the acinar parenchyma similar to those found in young German Shepherds with pancreatic atrophy.
Some studies5,6,7 have hypothesized that pancreatic atrophy is the consequence of an immune-mediated destruction of acinar cells. These studies have identified a subclinical stage, which precedes the stage of complete atrophy (and hence of clinical symptoms), characterized by a marked infiltration of T-cells as well as by the activation of humoural immunity and the presence of pancreas-specific serum antibodies. This may justify the hypothesis that PAA is preceded by an autoimmune lymphocytic pancreatitis.
The pathophysiology of PAA is currently considered multifactorial, presumably caused by multiple factors, among which also a genetic predisposition. Limited studies exist on environmental, infectious or non-infectious factors, which may have an impact on the onset or evolution of PAA. One study hypothesized that stress could also be among the triggering factors. In the cat, chronic pancreatitis is the main cause of EPI, while in the dog its pathophysiologic role still has to be precisely defined. The fibrosis and atrophy, which result from chronic inflammation, may however surely destroy a sufficient amount of pancreatic tissue to induce clinical signs (Fig. 1).
One study4 reports that the age of onset of the clinical signs correlates with the pathophysiological cause; patients presenting clinical signs at an adult age are presumably affected by chronic pancreatitis, while in younger subjects an immune mediated cause is more likely. Theoretically, a pancreatic duct obstruction may also be the cause of a deficiency of digestive enzymes within the intestinal lumen, with consequent clinical signs, even in the presence of an adequate production. If the duct obstruction persists, over time the pancreas may show signs of pancreatitis, with consequent atrophy, which in turn may result in EPI. The most probable cause of duct obstruction is a pancreatic adenocarcinoma; neoformations affecting the surrounding organs, such as the duodenum, may also potentially induce such a condition. Congenital pancreatic hypoplasia or aplasia is a possible theoretical cause of EPI, although this has never been conclusively proven; this etiology may be suspected when EPI-affected patients are very young. Theoretically, hyperplasia of somatostatin-producing cells (somatostatin inhibits pancreatic secretion) could also be the cause of an enzymatic deficiency, with consequent clinical signs. A selective deficiency of one of the digestive enzymes is not considered sufficient to cause clinical signs. In humans, pancreatic lipase deficiency is an exception to this rule, and a recent veterinary report8 has also hypothesized that a selective deficiency of this enzyme may have caused clinical signs in a 4-month-old Husky. In this patient, serum TLI (Tripsin Like Immunoreactivity) was normal, while pancreatic lipase was reduced and the resolution of the clinical signs was obtained with enzymatic supplementation.
Pancreatic enzymes are fundamental for the correct digestion of nutrients and their deficiency causes the accumulation of undigested material within the intestinal lumen. This scenario is at the basis of osmotic diarrhoea, microbial flora proliferation, dismicrobism, enteritis and consequently weight loss. In addition, the exocrine pancreas has functions other than the purely digestive ones, and which are crucial for the wellbeing of the GI tract. As an example, it secretes bicarbonates, which buffer gastric acid; should this not happen, the duodenal pH may decrease, thus compromising the activation of pancreatic and of brush border enzymes, with consequent maldigestion and dismicrobism. In addition, the pancreas secretes trophic factors which adjuvate the intestinal mucosa; the deficiency of these may contribute to malabsorption. Differently than in humans, in the dog and cat the pancreas is the main producer of intrinsic factor, which is indispensable for the absorption of vitamin B-12, the deficiency of which is typically associated with EPI.
CLINICAL SIGNS
The main clinical sign of EPI is weight loss (Fig. 2). In most cases diarrhoea is also present, typically grey and yellowish in colour, greasy in appearance and poltaceous in consistency (Fig. 3). The faecal volume is usually increased, as well as the frequency of defecation. Occasionally, watery diarrhoea and defecation urgency are present. Patients with EPI may present polyphagia, coprophagia as well as pica. Borborygms and flatulence are often present; in some patients aggressiveness and nervousness have been reported, presumably secondary to abdominal discomfort. A poor hair coat may be present. In patients with an inflammatory gastroenteritis associated with EPI, vomiting and dysorexia may be present. In general, the clinical manifestations of EPI are not specific and overlap with those encountered in the presence of an enteropathy of various origins. It is therefore important for the clinician to associate and correlate all the clinical data, meaning: signalment, stool appearance, anorexia, diarrhoea and polyphagia.
DIAGNOSIS
The diagnosis of EPI is based on the confirmation of a functional deficit of the exocrine pancreas. Standard laboratory tests are not useful in the diagnosis of EPI; in some cases hypocholesterolaemia and an increase in alanine aminotransferase can be documented, secondary to the increase in the uptake of hepatotoxic substances by the small bowel. Amilase and lipase are of no value in the diagnosis of EPI. Various tests have been used in the past to assess pancreatic function: the PABA test (para-aminobenzoic acid), the plasma turbidity test, the search for starch, fats and muscle fibres in the stools. These are all indirect assays as they assess the function of the entire GI tract and are not specific for the pancreas. The faecal proteolytic activity assay should be a valid test, as protein digestion is mostly dependent on pancreatic trypsin and chymotrypsin; in reality this assay has given variable results with frequent false positive and false negative results. These tests should be carried out on more than one sample and at different time points, as daily variations are present and healthy dogs may also have a low proteolytic activity. In conclusion, in view of their limited applicability and sensitivity, the use of these tests is not recommended. Faecal elastase is a species-specific ELISA test. Elastase is one of the enzymes released by the pancreas within the intestinal lumen and hence into the faeces; in the course of EPI, faecal elastase is not identifiable; a value under 10 µg/g is considered indicative. In spite of having a good sensitivity and specificity, the positive predictive value of this test is below 60%14 According to a recent study,10 this test can give false positive results in patients with a reduced level of cholecystokinin, and hence with a reduced stimulation of the pancreas. This may happen in patients with a chronic bowel disease, with a reduced number of neuroendocrine cells and a consequent reduced stimulation of pancreatic secretion and hence with a reduction in the faecal concentration of elastase. It has been hypothesized that this test could be used to identify EPI in its early stages, when the TLI is not yet reduced;9 further studies are however necessary to confirm this.
Serum Trypsin-Like Immunoreactivity (TLI) is currently the most commonly used test in the diagnosis of EPI. This test, an immunological assay, which makes use of a species-specific antibody, identifies the presence of trypsin or of its precursors (Trypsin-like) in the blood. Trypsinogen is released by the pancreas into the bowel by means of the pancreatic ducts, while a small amount flows into the circulation and may hence be measured in the blood; the trypsinogen present within the intestinal lumen is not absorbed, even in the presence of an intestinal disease. The test, a radioimmunometric and/or Immulite (chemiluminescence) assay, measures the concentration of the mass of trypsinogen and of cationic trypsin, as well as of some cationic trypsin molecules bound to proteinase-inhibitor molecules.
The serum TLI assay is species-specific (c-TLI) and is highly specific (100%) in the diagnosis of EPI. The test should be carried out with the patient fasted for at least 8-12 hours, as a post-meal value increase - although brief and transient - may be present. Renal function should also be controlled, as a reduced glomerular filtration may be the cause of a c-TLI increase. Intense lipaemia may also alter the results. The reference range for a healthy dog, in the laboratory used by the Author, is between 5-35 µg/L. An increased TLI may be reported in the presence of acute pancreatitis, pancreatic necrosis and following treatment with high dose cortecosteroids. A decreased TLI is principally found in the presence of EPI; it can also be found in the presence of chronic pancreatitis, when this has caused a reduction in the functional mass of the organ. When the TLI value is < 2,5 µg/L (or very low for the reference range used) the diagnosis of EPI is practically certain, and signifies and end-stage pancreatic insufficiency. In the initial or early stages of EPI, the pancreatic tissue may however produce sufficient amounts of enzyme so as to maintain the TLI value within the reference range. Furthermore, in the course of pancreatitis, although in the presence of an inferior functional pancreatic mass, the remaining damaged cells may release a greater amount of enzyme. In such a scenario, the TLI may fall within the normal range notwithstanding the presence of EPI. Consequently, although the specificity of this test is extremely high, the same is not true for its sensitivity in the diagnosis of EPI. In case of doubt, in order to facilitate the diagnosis of EPI it is recommended to repeat the test one or more times, also after a short lapse of time. The repetition of the test is a suitable strategy also in those cases in which the TLI value is between 2,5 and 5 µg/L (or of values just slightly below the normal range according to the laboratory used), in the so-called “grey area”. This condition is defined as subclinical EPI. In these patients a repetition of the test may allow to confirm a progression of EPI, or may well show a possible return to normal values. In some cases the values persistently remain within the “grey area”, in the absence of clinical signs; to date, the meaning of persistently slightly decreased TLI values is not yet clear. In humans, this may take place in the presence of chronic pancreatitis, as well as in the presence of non-pancreatic diseases. In the dog, to confirm EPI it is also possible to reassess the TLI following and endogenous (food) or exogenous (enterohormones) stimulation. One study,11 which investigated this condition and used the term subclinical EPI (SEPI), suggested the repetition of the TLI assay every 3-6 months, as well as an exogenous stimulation of the pancreas. Should the patient be affected by only pancreatic lipase deficiency, the TLI test may result normal, as may happen in the presence of pancreatic duct obstruction; both these conditions are however rare. Measurement of serum pancreatic lipase13 is not a sensitive test for EPI, as this enzyme is much larger than trypsinogen and has a positive charge, thus being rejected by the glomerular membrane; it is then slowly eliminated by the kidneys leaving an elevated amount of residues, which consequently persist in the blood. A low serum value is useful in diagnosing a selective lipase deficiency in subjects with clinical signs compatible with EPI and with a normal TLI.8
In the course of EPI, a reduction in cyanocobalamin (vitamin B12) values is common. Vitamin B12 is of food origin and is absorbed by the ileum, via a process favoured by the intrinsic factor and a not excessively acid luminal pH. The intrinsic factor is principally produced by the pancreas and in minimal part by the gastric mucosa, while the luminal pH is made less acid by bicarbonates produced by the pancreas. In view of the above reasons, in the course of EPI vitamin B12 is consequently reduced; furthermore, the concomitant bacterial overgrowth, which is frequent in the course of EPI, contributes to the consumption of cyanocobalamin. On the contrary, in the course of EPI the serum concentration of folates may result increased, in view of their increased production by bacteria and the increased absorption in the presence of a more acid endoluminal pH.
In cases in which the clinical history, signalment and serum TLI values leave doubts about the origin of the pancreatic dysfunction, diagnostic imaging is used. This may happen when a duct obstruction, a neoplastic process or a reversible inflammatory process are suspected. Pancreatic biopsies may be performed via laparotomy (Fig. 4), laparoscopy or with a cytological ultrasound-guided fine needle biopsy. The fine needle biopsy is not a sensitive test in the course of EPI, while it can be useful in the presence of neoplastic or acute inflammatory conditions.
THERAPY
Patients affected by a subclinical form of EPI, in the absence of clinical signs, do not require treatment. Immunosuppressant therapies have been used as a preventive treatment, however the results are questionable, as the subclinical form may persist in these patients for their entire life independently from the medical therapy used. Immunosuppressant therapies are furthermore not exempt from adverse events. As the factors which influence the progression of the disease are not known, a preventive therapy is consequently not possible. When the subclinical form is associated with GI clinical signs, a medical therapy for EPI is recommended; however, should the clinical signs persist, other concomitant GI disorders cannot be excluded and must therefore be identified and treated.
In the course of EPI, supplementation with digestive enzymes is the mainstay of treatment. Numerous suitable products are available for this purpose. Bovine and porcine dried pancreatic extracts, as well as raw morselled pancreas, have proven equally effective. Treatment is usually started with a teaspoon of extract every 10 kg of body-weight, administered with each meal; once the clinical response has been achieved, the dosage is reduced to the minimum effective dose. Raw pancreas can be of bovine, porcine or, less frequently, of sheep-goat origin. The pancreas is administered at the dose of 50-100 gr per meal, for dogs weighing between 25 and 30 kg, or at the dose of 20-30 gr for each 10 kg of body weight of the patient. Pancreatic enzymes are also available in the form of tablets or capsules, however based on the known studies these seem less effective compared to powder formulations. Should fresh pancreas be used, this may be divided into portions sufficient for a meal and then frozen, as also in this form the enzymatic activity is preserved for long periods of time. The use of this type of formulation cannot exclude a possible infectious contamination by BSE (bovine spongiform encephalopathy), for the bovine pancreas, and Aujeszky’s disease, for the porcine pancreas. The sheep-goat pancreas could also be infected with Echinococcus. In reality these risks are also present with the powder formulations and in any case to date no cases of this complication have been reported. Enzymatic supplementation may also be done with pre-incubation, that is maintaining the enzymes in contact with the food for 10-15 minutes. Based on existing studies this manoeuvre does not however seem to improve the efficacy16,17 of the therapy. Pre-incubation apparently does not work as the enzymatic activity is enhanced within the organism by the body temperature, the pH, the presence of lipid micelles and additional enzyme catalysis. This notwithstanding, some owners anecdotally report a relevant improvement in faecal consistency and symptoms with pre-incubation. This further confirms that each patient must be managed individually and that it is advisable to modify the variables of the therapeutic protocol without prejudice and based on the clinical response.
A recent study18 reported the presence of oral cavity bleeding in 3 out of 25 dogs undergoing enzymatic supplementation. Should this complication be present, once coagulation tests have been carried out to exclude a vitamin K deficiency the dose of the enzymes should be decreased; should the new dose not be very effective in the management of EPI symptoms, a long pre-incubation is suggested. In the above mentioned study, this latter strategy resulted effective in inhibiting the relapse of oral bleeding. In humans, other complications have been described in association with enzymatic supplementation, such as fibrosing colopathy, hyperuricosuria and colon stenosis. Should the supplementation not achieve the expected results, the type of enzymatic formulation may be changed or fresh pancreas may be used; it is also possible, and recommendable, to increase the dose, multiplying it by two or by three. In some cases it is also possible to integrate the enzyme treatment with antacids. This strategy results from the fact that a relevant percentage of enzymes is destroyed by the acid environment of the stomach, and a rise in pH could increase duodenal enzymes and consequently improve the therapeutic response; on the other hand, this strategy may cause a reduction in gastric-derived lipase. As previously mentioned, a perfect treatment does not exist and it is therefore legitimate to make an attempt with anti-H2 drugs, and also with omeprazole, which in humans turned out to be the most efficient drug for this purpose.
The nutritional management of EPI patients has been the object of many studies carried out over the years. Initially, it was suggested to feed these dogs with hyperdigestible, low-fat diets;19,20 more recently, experimental studies21 carried out on cases of induced EPI reported a better clinical response with a high-fat, high-protein diet, combined with enzyme supplementation. A reduced fat content was traditionally suggested for all GI disorders, in view of the complexity of their digestive process. In addition, endoluminal bacteria may metabolize the undigested fats into hydroxilated fatty acids, which induce osmotic diarrhoea of the colon and may deconjugate biliary acids, thus blocking digestion and the absorption of fats. These considerations are currently considered partially obsolete, as in the dog and cat the intestine is specialized in the digestion of fats, which are in fact the most digestible nutrient. A recent study on an experimental model of EPI has shown that the digestion and absorption of fats was greater when the enzyme supplementation was combined with a fat-rich diet. A recent study on the prognostic factors in the course of EPI22 showed that low-fat diets do not fare better than other diets in the management of EPI.
In general, during the initial treatment phase it is recommended to maintain the same diet taken by the patient before the diagnosis, if of good quality. If the clinical condition does not improve, a commercial or homemade hyper-digestible, low-fibre (fibre interferes with the absorption of lipids), low-fat diet may be used. Some patients instead improve considerably using a homemade, fresh and raw diet. A hypoallergenic diet, usually with low cereal content, may also be used. In the selection of the diet it is necessary to recall a fundamental concept in the treatment of EPI: each patient is different from the others and hence the decision on the diet should not be dogmatic; when the clinical response is not satisfactory, one or more changes in the diet are necessary. At the beginning of the treatment the meal is initially divided into three portions; if the patient is underweight, 150% of the theoretical maintenance requirement may be administered, with a subsequent dose reduction when the patient returns to a normal weight. The meal is to be administered at room temperature or, at the most, slightly warm, as cold, or high temperatures, may inactivate the enzymes. When capsules are used, these should be added to the meal intact and should not be opened. Some owners report an improvement by also morseling the food or by softening it, maybe because this action increases the surface contact of the enzymes with the food. No scientific paper has however confirmed this observation.
The bacterial overgrowth secondary to EPI results from both the loss of pancreatic juice bacteriostatic agents and from the availability of undigested food substrates within the intestinal lumen; some patients show a clinical improvement with antibiotic therapy, and tylosin is usually a good choice. Tylosin may be used with a broad range of dosages: 5-25 mg/kg once or twice a day. When used at 5 mg/kg it acts as a prebiotic. Metronidazole, oxytetracycline and amoxicillin may also be used. After the start of the antibiotic therapy the clinical response is usually observed within 3-4 weeks. On the basis of scientific publications the use of antibiotics does not however seem to have an impact on survival.
Cobalamindeficiency may be present also in the absence of secondary SIBO and its parenteral supplementation is necessary; the dosage varies between 150 and 250 µg in the cat and between 250 and 1200 µg in the dog, depending on the size of the animal; the administration must be done subcutaneously and not via the oral route. The supplementation should be administered every week, for 6 weeks, then every other week for a further 6 weeks, and with a further additional dose after one month and after 2 months. After this treatment protocol serum cobalamin usually returns to normal, or at times to values higher than normal.
Although the deficiency of liposoluble vitamins in the course of EPI has been reported,23 the usefulness and modality of their supplementation has not yet been studied and an excessive supplementation could cause negative adverse events. Vitamin E supplementation (400-500 IU orally every 24 hours for 1 month) has been reported anecdotically, however the real benefit of such supplementation has not yet been studied. The use of antacids (cimetidine) has been considered in one study;24 their use is based on the fact that a high percentage of lipase is inactivated by gastric acidity, consequently an increased stomach pH should have a beneficial effect; on the other hand an increased gastric pH reduces the availability of gastric lipase. In a study on prognostic factors, the use of cimetidine did not improve both the initial response to therapy and the long-term prognosis.
When in an EPI patient the response to the initial base therapy is not satisfactory, all the existing variables are to be reconsidered, such as the type of enzymes used, the administration modality, the amount and type of diet. Should the patient continue to show clinical signs also after a change in strategy, other concomitant disorders may be possibly present, such as IBD or diabetes mellitus. Diabetes is more frequent in cases of EPI associated with chronic pancreatitis and if present, diabetes must be adequately treated, with both diet and insulin therapy. Although hypothesized by many authors, the presence of a concomitant inflammatory bowel disease (IBD) has not yet been extensively studied; the administration of glucocorticoids is therefore not advisable as a first-line therapy and should instead be considered in case of persistence of the clinical signs and in the presence of an histologic examination compatible with IBD.
PROGNOSIS
EPI is a chronic disease, which theoretically lasts for the entire life of the patient, even if anecdotal cases of disease resolution have been reported. Collaboration by the owners is fundamental for the success of the treatment; once the correct combination between diet, enzyme supplementation and support therapy has been established, EPI-affected patients can enjoy an adequate quality of life for years. Although studies to identify the prognostic factors in the course of EPI have been carried out, the only prognostic factor linked to an unfavourable prognosis is cobalamin deficiency. In the study by Batchelor,22 on 178 dogs, the response to the initial treatment was good in 60%, partial in 17% and poor in 23%. Dogs with elevated folate levels or which underwent an antibiotic therapy seemed to have a poorer response to the initial treatment. Nineteen (19%) per cent of the patients undergoing treatment were euthanized within 1 year, however the overall mean survival was > than 5 years. Neither the type of enzymes used, nor the use of antibiotics or of anti-2H drugs correlate with a longer survival; the same resulted true for the age, sex or breed of EPI patients.
PANCREATIC INSUFFICIENCY IN THE CAT
In the cat, pancreatic insufficiency is a rare event. The most frequent cause of EPI is chronic pancreatitis; cases secondary to Eurytrema procionis infestation have been reported. Pancreatic adenocarcinoma and duct obstruction may also cause atrophy of the acinar tissue; anecdotal reports of conditions histologically indistinguishable from the acinar atrophy of the pancreas typical of the dog have also been reported, although it is not clear if the pathophysiology typical of the canine species is applicable also to the cat.
In two retrospective studies25,26 on 15 cases of EPI in the cat, the most frequent clinical sign was weight loss, followed by diarrhoea with soft, voluminous and foul-smelling stools, vomiting, polyphagia, anorexia, lethargy as well as faecal incontinence. The presence of polyphagia is variable. The physical examination may often reveal poor overall physical conditions, anorexia, thickened intestinal loops and especially a “wet” coat, typically in the perineal region. Disorders typically associated with EPI are frequently found in the cat, such as lymphoplasmacellular enteritis, gastritis, lower urinary tract infections and liver diseases. Diabetes mellitus is considered a much more common complication of EPI in the cat, compared to the dog, presumably because chronic pancreatitis is the main predisposing pathophysiologic condition and in the cat around 50% of diabetics are affected by pancreatitis. Although hyperglycaemia is a relatively common finding, in reality in publications only 4 cases of diabetes mellitus associated with EPI26,27,28 have been reported.
Just like in the dog, haemato-biochemical examinations are not very indicative, although they can report: lymphopenia, anaemia, neutrophilia, eosinophilia and increased liver enzymes. A cobalamin assay (reference range: 290-1499 ng/L) frequently shows decreased values, as in the cat the pancreas is the biggest producer of intrinsic factor. Folates (reference range: 9,7-21,6 µg/L) may be increased, but also decreased.
Indirect diagnostic imaging techniques do not reveal any particular anomaly. TLI measurement, a sensitive and specific assay for pancreatic function (fTLI < 12ng/L), has been validated also in the cat and its measurement is fundamental to confirm the diagnostic suspicion. All other indirect tests have been abandoned, and even the measurement of faecal proteolitic activity, assayed using azocasein and azoalbumin based methods, is not very specific and repeatable compared to f-TLI.
EPI treatment in the cat is similar to that in the dog; when using dry powder, the dose is of about half a teaspoon per meal; if raw pancreas is used, the dosage is of 30-60 gr per cat for each meal. Preventive incubation and antacid therapy are not necessary also in the cat. In the cat, cobalamin supplementation is fundamental for therapeutic success, to be administered at the dosage of 150-250 µg subcutaneously, once a week, for 1 or 2 months. If necessary, folates may also be supplemented, orally (400 µg per day), as well as vitamin K. Also in the cat, failure of response to treatment may be secondary to other concomitant disorders such as IBD, SIBO or diabetes mellitus.
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