Exocrine pancreatic insufficiency

Progressive loss of pancreatic acinar cells ultimately leads to malabsorption due to inadequate production of digestive enzymes. The functional reserve of the pancreas is considerable, however, and signs of exocrine pancreatic insufficiency (EPI) do not occur until most of the gland has been destroyed. Although pancreatic enzymes perform essential digestive functions, alternative pathways of digestion for some nutrients do exist. Following experimental exclusion of pancreatic secretion from the intestine, dogs can still absorb up to 63% of ingested protein and 84% of ingested fat. This residual enzyme activity probably originates from lingual and/or gastric lipases and gastric pepsins, from intestinal mucosal esterases and peptidases, and, in young animals, from bile salt-activated lipase in milk. Nonetheless, when exocrine pancreatic function is severely impaired, these alternative routes of digestion are inadequate and clinical signs of malabsorption occur. Feline EPI is much less common than EPI in dogs, but development of a reliable test for fTLI has shown the disease to be far more prevalent than previously realized.

Aetiology

Spontaneous development of pancreatic acinar atrophy (PAA) in previously healthy adult animals appears to be unusually common in dogs, in which it is the most common cause of EPI (). Similar conditions occur sporadically in other species, and the author is aware of cases of a histologically identical condition in cats. Recent studies have revealed that in German Shepherd Dogs and Rough Collie breeds PAA is preceded by subclinical, possibly autoimmune, lymphocytic pancreatitis that leads to acinar cell destruction. Since islet cells are spared these patients do not develop diabetes mellitus.

While chronic pancreatitis resorting in progressive destruction of pancreatic tissue is a common cause of EPI in adult human beings and cats, this is a rare cause of EPI in dogs. Animals with EPI and coexistent diabetes mellitus probably have chronic pancreatitis, since pancreatic inflammation is likely to damage both endocrine and exocrine tissue, in contrast to the selective acinar cell damage in PAA.

Congenital deficiencies of individual pancreatic digestive enzymes or of intestinal enteropeptidase have not been described in dogs or cats. Occasionally, young dogs are seen that have signs of EPI and sometimes diabetes mellitus from a very early age, and congenital pancreatic hypoplasia or aplasia may be the underlying cause. Smouldering subclinical EPI is occasionally identified in dogs with immune-mediated lymphocytic pancreatitis that has not progressed to frank PAA.

Finally, EPI has been reported as a complication of proximal duodenal resection and cholecystoduodenostomy in cats. This reflects the absence of dual pancreatic ducts in this species, with blockage of pancreatic secretion occurring as a result of damage to the major duodenal papilla. Pancreatectomy will also lead to EPI.

Pathophysiology

Nutrient malabsorption in canine EPI does not arise simply as a consequence of failure of intraluminal digestion. Morphological changes in the SI of some dogs with EPl have been reported and studies of naturally occurring, and experimental, EPI in several species have revealed abnormal activities and impaired function of mucosal enzymes, indicated by abnormal transport of sugars, amino acids and fatty acids. Absence of the trophic influence of pancreatic secretions, true bacterial overgrowth in the SI and endocrine and nutritional factors may all contribute to this pathology.

Small intestinal mucosa: EPI in several species is associated with reducad degradation of exposed brush border proteins, such as maltase and sucrase, as a consequence of decreased pancreatic protease activity within the gut lumen. It has been suggested that accumulation of these brush border membrane proteins may interfere with normal absorption.

Small intestinal microflora: Bacterial overgrowth in the lumen of the SI is common in both untreated and treated dogs with EPI. Changes in the intestinal microflora may arise secondary to loss of the antibacterial properties of pancreatic juice or as a consequence ot disturbed intestinal immunity or motility.

The pathological changes associated with bacterial overgrowth depend on the type of bacteria involved and the chronicity of the overgrowth. In those dogs with increases in aerobic and facultative anaerobic bacteria, activities of brush border enzymes are often increased as described above. In contrast, when the overgrowth includes obligate anaerobic bacteria there is often a decrease in many enzyme activities, and perhaps partial villous atrophy (). In both circumstances bacteria may impair absorption by competing for nutrients and by changing intraluminal factors.

Pancreatic regulatory peptides and glucose intolerance: Histopathological examination of the pancreas from dogs with PAA reveals almost total atrophy of acinar tissue but plentiful, albeit highly disorganized, islet tissue containing many insulin-, glucagon-, somatostatin- and pancreatic polypeptide-immunoreactive cells. These morphological changes may account for subnormal basal plasma insulin concentrations that have been reported in dogs with PAA. In patients with EPI secondary to pancreatitis there may be frank diabetes mellitus secondary to islet cell destruction.

Nutritional status: Many patients with EPI have been suffering from malabsorption for a considerable period of time before a diagnosis is made. Thus, the clinical and pathophysiological features associated with EPI may in some instances be due to malnutrition rather than EPI per se. Oral and intravenous glucose tolerances are abnormal in untreated dogs with PAA, although diabetes mellitus has not been reported in these dogs. Treatment of PAA is followed by normalization of intravenous glucose tolerance, although basal plasma insulin concentrations remain subnormal. It is probable that the abnormalities in glucose homeostasis are related, at least in part, to metabolic changes associated with the catabolic and undernourished state of many untreated dogs with EPI. Malnutrition in rats impairs the capacity to maintain protective mucosal mucin content, and accelerates the development of blush border enzyme deficiency in intraluminal bacterial overgrowth.

Mildly or severely subnormal serum cobalamin concentrations are commonly observed in dogs and cats with EPI. Deficiencies of pancreatic proteases, as well as pancreatic intrinsic factor, could contribute to cobalamin malabsorption, and overgrowth of cobalamin-binding bacteria in the proximal SI is a likely additional contributory factor. Serum cobalamin concentrations rarely normalize following treatment with oral pancreatic enzymes. Intestinal dysfunction due to persistent cobalamin deficiency may be a contributory factor in those patients with EPI and a suboptimal response to enzyme replacement therapy. Cobalamin deficiency might also be responsible for the anorexia reported in some patients with EPI.

Serum tocopherol (vitamin E) concentrations are often severely subnormal in EPI and do not increase in response to treatment, perhaps because treatment does not return fat absorption to normal or because bacterial overgrowth persists. TocophefOl deficiency may cause insideous pathological changes in erythrocyte membranes, smooth muscle, the central nervous system, skeletal muscle and the retina.

Subnormal serum concentrations of vitamin A have also been observed in dogs with EPI but no associated signs of deficiency have been reported. Vitamin Kresponsive coagulopathy occurs rarely in patients with EPI, but is more common in affected cats than dogs.

Diagnosis

History: Dogs and cats with EPI usually have a history of weight loss but a normal or increased appetite. Polyphagia is often severe and owners may complain that dogs ravenously devour all food offefed to them and scavenge from waste bins but some dogs have periods of inappetence. Coprophagia and pica are also common in dogs. Water intake may also increase in some dogs and in chronic pancreatitis there may be polyuria and polydipsia due to diabetes mellitus. Diarrhoea often accompanies EPI but can be very variable in character. Most owners report frequent passage of large volumes of semi-formed faeces, although some patients have intermittent or continuous explosive watery diarrhoea, while in other instances diarrhoea is infrequent and is not considered a problem. Diarrhoea generally improves or resolves in response to fasting. Feeding a low fat or low carbohydrate diet may also decrease or eliminate diarrhoea.

There may be a history of vomiting and commonly there is marked borborygmus and flatulence with sometimes apparent episodes of abdominal discomfort. PAA is prevalent in young German Shepherd Dogs and thus EPI is often initially suspected because of the age and breed of the affected dog. It must be emphasized, however, that even in young German Shepherd Dogs SI disease is more prevalent than EPI and that PAA may occur in a wide variety of breeds at any age. Similarly, most cats with polyphagia, weight loss and diarrhoea are ultimately diagnosed as having SI disease associated with severe cobalamin deficiency; these cases are clinically indistinguishable from those with EPJ without appropriate diagnostic testing.

Clinical signs: Mild to marked weight loss is usually seen in association with EPI. Some dogs are very emaciated at presentation with severe muscle wasting and no palpable body fat and, in extreme cases, dogs may be physically weak as a result of loss of muscle mass. The haircoat is often in poor condition and some animals may give off a foul odour f because of haircoat soiling with fatty faecal material and the passage of excessive flat us. Cats with EPI may exhibit a greasy, wet-looking and generally unkempt hair coat, especially in the perineal region, which may in part reflect severe cobalamin deficiency ().

Laboratory tests: The history and clinical signs of EPI do not distinguish the condition from other causes of malabsorption () and while replacement therapy with oral pancreatic enzymes is generally successful, response to treatment is not a reliable diagnostic approach.

In PAA, extreme atrophy of the pancreas is readily observed on gross inspection at either exploratory laparotomy or laparoscopy. In chronic pancreatitis it may be impossible to gauge accurately the amount of residual exocrine pancreatic tissue because of severe adhesions and fibrosis. These procedures involve unnecessary anaesthetic and surgical risks and their use for diagnostic purposes cannot be recommended, given the availability of reliable non-invasive tests.

Routine laboratory test results are generally not helpful in establishing the diagnosis of EPI. Serum alanine aminotransferase (ALT) activities are mildly to moderately increased and may reflect hepatocyte damage secondary to increased uptake of hepatotoxic substances through an abnormally permeable SI mucosa. Other routine serum biochemical test results are unremarkable, except that total lipid, cholesterol and polyunsaturated fatty acid concentrations are often reduced. Serum protein concentrations are usually normal even when patients are severely malnourished. Lymphopenia and eosinophilia are not uncommon but other abnormalities should be considered as evidence for additional, or alternative, underlying disorders.

Canine serum amylase, isoamylases, lipase and phospholipase A2 activities are only minimally reduced in EPI, indicating that non-pancreatic sources of these enzymes are clearly present in dogs. The most reliable and widely used test currently available is assay of serum TLI.

Trypsinogen is synthesized exclusively by the pancreas and measurement of the serum concentration of this zymogen by species-specific radioimmunoassay provides a good indirect index of exocrine pancreatic function in the dog. Serum TLI concentration is both highly sensitive and specific for the diagnosis of EPI, since concentrations are dramatically reduced compared with those in normal animals and those with small intestinal disease (). Marked reductions in serum TLI (to <2 μg/I in dogs or 8 μg/I in cats) may even precede signs of weight loss or diarrhoea. Utilization of this test is simple in that analysis of a single serum sample obtained after food has been withheld for several hours is all that is required. Serum TLI is very stable and samples can therefore be mailed to an appropriate laboratory for analysis. It is important to remember that there is no cross-reactivity between canine and feline TLI and that serum fTLI values in normal cats, as well as in cats with EPI, are greater than those in dogs. As noted above, at the time of writing fTLI assay is available only from the author’s laboratory at Texas A&M University.

Other tests used for diagnosis of EPI include: assay of faecal proteolytic activity using azoprotein, gelatin or radial enzyme diffusion methods; specific assay of faecal pancreatic elastase in dogs; the bentiromide (BTPABA) test; plasma turbidity after oral fat administration; and microscopic examination of faeces. Many of these tests give significant proportions of false-negative and false-positive results and their use even as crude ‘screening’ tests is not recommended. Furthermore, their availability is limited and even when properly performed they are inconvenient and expensive. When EPI is suspected in cats or dogs, serum TLI should be assayed.

Exocrine pancreatic insufficiency: Treatment

Enzyme replacement: Most dogs and cats with EPI can be successfully managed by supplementing each meal with pancreatic enzymes present in commercially available dried pancreatic extracts. Numerous formulations of these extracts are available (tablets, capsules, powders, granules) and their enzyme contents and bioavailabilities vary. Addition of approximately two teaspoons of powdered pancreatic extract per 20 kg of bodyweight to each meal is generally an effective starting dose. Extract should be mixed with a maintenance food immediately prior to feeding. Two meals a day are usually sufficient to promote weight gain. Dogs will generally gain 0.5 — 1.0 kg per week and diarrhoea and other clinical signs, such as polyphagia and coprophagia, often resolve within 4 — 5 days.

As soon as clinical improvement is apparent owners can determine a minimum effective dose of enzyme supplement that prevents return of clinical signs. This varies slightly between batches of extract and also from patient to patient, probably reflecting individual variation in extrapancreatic digestive reserve. Most affected dogs require at least one teaspoonful of enzyme supplement per meal but lower doses may be adequate in cats and small dogs. One meal per day is sufficient in some dogs while others continue to require two. If available, chopped raw ox or pig pancreas (100 — 150 g per 20 kg of bodyweight), obtained from animals certified as healthy following appropriate post-mortem inspection, is an inexpensive alternative to dried extract. Pancreas can be stored frozen at  -20⁰ C for at least 3 months without significant loss of enzyme activity.

Effectiveness of enzyme replacement: While administration of pancreatic enzymes with food is generally successful, only a small proportion of the administered enzymes is delivered functionally intact to the SI and fat absorption does not return to normal. Pancreatic lipase is rapidly inactivated at the acid pH encountered in the stomach, while trypsin and some other pancreatic proteases, although relatively acidresistant, are susceptible to degradation by gastric pepsins. Efforts to increase the effectiveness of enzyme supplementation by pre-incubation of enzymes with food prior to feeding, supplementation with bile salts, neutralization or inhibition of gastric acid secretion and use of enteric-coated preparations have generally not proved effective.

Most notably, pre-incubation of food with enzyme powder for 30 minutes prior to feeding does not improve the effectiveness of oral enzyme treatment in promoting fat absorption in dogs with ligated pancreatic ducts. Gastric acid secretion may be reduced by administration of histamine H, receptor antagonists. Cimetidine administered 30 minutes prior to giving food mixed with pancreatic enzymes does improve fat absorption in dogs with ligated pancreatic ducts but does not decrease faecal wet or dry weight. Routine use of cimetidine is not recommended, however, given the expense of the drug and the fact that so many patients respond well when treated with enzymes alone. Oral antacids, such as sodium bicarbonate, aluminum or magnesium hydroxide, are inexpensive but do not increase the effectiveness of enzyme therapy.

Enteric-coated preparations have been formulated to protect enzymes from gastric acid but they are actually often less effective than powdered pancreatic extract. This may reflect selective retention of enteric-coated particles in the stomach whilst food is emptied or perhaps rapid intestinal transit preventing adequate enzyme release in the upper SI. Future enteric-coated preparations formulated specifically for cats and dogs may prove advantageous. Similarly, new preparations containing acid-resistant fungal or gastric lipases may prove to be effective and economical. Such new preparations are unlikely to help in management of patients with sub-optimal weight gain since they rarely improve after either increasing the dose of enzymes over that recommended above or giving cimetidine, suggesting that factors other than enzyme delivery to the SI are involved.

Dietary modification: Fat absorption does not return to normal despite appropriate enzyme therapy. Patients appear to compensate by eating slightly more than usual and, as with any individual, it is necessary to regulate the amount of food given in order to maintain ideal bodyweight. Some types of dietary fibre impair pancreatic enzyme activity in vitro and diets containing large amounts of non-fermentable fibre probably should be avoided. However, low fat diets merely impair calorie uptake and should not be fed. In order to overcome residual digestive deficits, the feeding of a highly digestible, low non-fermentable fibre diet may be beneficial. A non-blinded clinical study found that owners considered that their dogs generally did better (reduced flatulence and borborygmi, decreased faecal volume and frequency of defaecation) when fed a commercial highly digestible diet compared with the previously fed home-cooked or regular maintenance diets, but there was no difference in appetite, drinking, colour or consistency of faeces, or in coprophagy. Results of experimental studies to evaluate highly digestible diets have shown consistent reductions in faecal weight, but have not shown consistent benefit with Regard to fat digestibility. Highly digestible diets may be of value in promoting calorie uptake in those dogs with EPI that do not Regain normal bodyweight. These patients may also benefit from being fed a diet containing (or supplemented with) readily hydrolysed and absorbed medium chain triglycerides.

Vitamin supplementation: Dogs and cats with EPI may have severely subnormal concentrations of serum cobalamin (vitamin B12) and tocopherol (vitamin E). Serum concentrations of cobalamin in particular usually decrease following othefwise effective treatment with pancreatic enzymes. Clinical signs associated with deficiencies of these vitamins in dogs and cats have not been well documented but intestinal mucosal changes, myopathy, myelopathy and other abnormalities of nervous tissue have been reported in other species. Anorexia in dogs and an unkempt wet-looking haircoat in cats () have been documented in growing animals with cobalamin deficiency, but it is likely that additional non-specific signs occur in Older animals, including a general failure to thrive. Cats are particularly susceptible to development of severe cobalamin deficiency.

In the author’s experience, supplementation with large oral doses of tocopherol (5 — 25 IU/kg bodyweight given orally once daily with food for 1 month) is effective in returning serum concentrations to normal. In contrast, cobalamin must be given parenterally (100 — 250 μg i.m. or s.c. injection once a week for several weeks) to normalize serum concentrations. Long-term monitoring of serum cobalamin concentration, especially in cats, is recommended.

Malabsorption of vitamin A has also been demonstrated in association with EPI, as has vitamin K-responsive coagulopathy. Enzyme supplements do not correct or prevent these deficiencies. It should be noted that doses of individual vitamins in multivitamin preparations may be insufficient to normalize serum concentrations and that parenteral or very high oral doses may be required for adequate supplementation.

Antibiotic therapy: Dogs with EPI commonly have overgrowth of bacteria in the SI but in most cases this is a subclinical abnormality and affected individuals respond very well to treatment with oral enzyme replacement alone, even though the overgrowth often persists. Serum bile acid profiles also suggest altered intestinal microflora in cats with EPI. Altered intestinal microflora can cause malabsorption and diarrhoea, however, and in those individuals that do not respond to oral enzyme supplementation alone, antibiotic therapy may be of value. Oral oxytetracycline, metronidazole or tylosin may be effective in improving the clinical response in some of these patients. Chronic untreated bacterial overgrowth may cause mucosal damage that is only partially reversible following even prolonged antibiotic therapy, and this may explain why some animals fail to return to normal bodyweight. It is not clear whether a predisposition to recurrent colonization by an abnormal microflora persists following antibiotic therapy.

Glucocorticoid therapy: In those few patients that respond poorly to the above treatments, oral prednisolone at an initial dosage of 1 — 2 mg/kg q12h for 7 — 14 days is usually beneficial. This may be due to resolution of coexisting lymphocytic-plasmacytic gastroenteritis or other effects of glucocorticoids on the GI tract. Long-term glucocorticoid administration is generally unnecessary.

Exocrine pancreatic insufficiency: Prognosis

The underlying pathological process leading to EPI is generally irreversible and life-long treatment is required. It is particularly important to recognize that feline patients often require therapy in addition to enzyme replacement, most notably cobalamin supplementation. Given the expense of treatment it is reasonable in some cases to either repeat a serum TLI assay or withdraw enzyme supplement for a trial period every 6 months or so and observe the patient for recurrence of clinical signs. Pancreatic acinar tissue does have some capacity to regenerate and it is not inconceivable that following either pancreatitis or subtotal PAA, residual acinar tissue might regenerate sufficiently to normalize digestive function. Possible recoveries from clinically significant enzyme deficiency have been reported. However, in most cases treatment will be required for life but, providing owners are willing to accept the cost of enzyme replacement, the prognosis is generally good. Some patients may fail to regain normal bodyweight but these animals usually have total resolution of diarrhoea and polyphagia and are quite acceptable as pets. A high prevalence of mesenteric torsion and gastric dilatation and volvulus have been reported in German Shepherd Dogs and Rough follies with PAA in Finland but this has not been documented elsewhere.

Treatment of patients with diabetes mellitus and EPI due to chronic pancreatitis is likely to be troublesome and expensive. Diabetes mellitus secondary to chronic pancreatitis is potentially more difficult to regulate than simple diabetes in view of probable coexisting derangements in the secretion of glucagon and somatostatin. Moreover, anorexia and vomiting due to pancreatitis may further complicate treatment of diabetes mellitus.