Exocrine pancreatic insufficiency in dogs

Introduction

Exocrine pancreatic insufficiency (EPI) in dogs can cause poor absorption and digestion of food, with affected animals showing a progressive and serious deterioration in their health status. The veterinarian must know which breeds are predisposed to the problem and should be familiar with the clinical presentation, as well as being aware that concomitant disease may also be present. The clinician should therefore be alerted to the possibility of EPI when presented with a dog that shows one or more of the signs typically encountered with the disease, which will allow appropriate diagnostic tests to be instigated.

EPI – an overview

Exocrine pancreatic diseases have a significant prevalence in small animals yet are often underdiagnosed. Diagnosis can sometimes be complicated due to the presence of non-specific clinical signs, the possibility of concomitant disease, and difficulties in interpreting laboratory results and imaging tests. The most common disease processes of the exocrine pancreas are pancreatitis and exocrine pancreatic insufficiency; however the exocrine pancreas can also be affected by neoplastic processes that, although rare in small animals, can be confused with other lesions such as cysts, pseudocysts, or pancreatic abscesses.

The exocrine pancreas is responsible for the secretion of various substances that contribute to several important functions, including digestion of proteins, carbohydrates, and lipids (via digestive enzymes); helping to neutralize the duodenum (via bicarbonate, chlorine and water); intervening in the absorption of cobalamin (via intrinsic factor); and regulating the bacterial flora of the small intestine (via antibacterial proteins). EPI is a disorder of the gastrointestinal tract characterized by insufficient production of digestive enzymes by the pancreatic acinar cells; clinical signs will appear when over 90% of exocrine pancreatic function is lost.

Causes of EPI

Histopathological biopsy is required to confirm the underlying etiology of EPI, so in most cases a simple diagnosis is usually made based on the patient's history, laboratory results and/or imaging tests. However, literature data points to pancreatic acinar atrophy and chronic pancreatitis as the most probable causes of canine EPI.

Pancreatic acinar atrophy (PAA)

This is the most common cause of EPI in dogs, especially in breeds such as the German Shepherd, the Rough Collie, the Eurasier, and the Chow Chow 1. Studies in these breeds indicate the presence of an autoimmune process in genetically susceptible individuals, with the development of progressive lymphocytic infiltration that causes gradual destruction of the acinar tissue. Endocrine function is usually not affected. EPI is also presumed to be hereditary in nature, although this is not entirely understood at present, with complex multiple genetic and environmental factors likely involved in its etiopathogenesis 2. Two stages have been identified in PAA progression: a subclinical phase and a clinical phase. The progression from the first to the second phases is unpredictable, with some dogs taking years to reach the clinical stage whilst others may never show clinical signs. The subclinical phase is characterized by partial acinar atrophy in which the affected dog shows no clinical signs. As tissue inflammation and destruction progresses, severe atrophy of the tissue develops, leading to the second phase in which the clinical signs characteristic of insufficient pancreatic function become apparent. Some authors suggest the term immune-mediated atrophic lymphocytic pancreatitis to describe the pathological changes that define the phase that precedes the terminal atrophy of the acinar tissue 1.

Chronic pancreatitis

This is the most frequent cause of EPI in cats and the second most common cause in dogs, especially in breeds such as the Cavalier King Charles Spaniel and Cocker Spaniel 1. Unlike PAA, with chronic pancreatitis there is usually a progressive destruction of both endocrine and exocrine pancreatic tissues. It is therefore necessary to consider the possibility of concurrent diabetes mellitus, chronic pancreatitis, and EPI in these patients, or to be alert to signs of EPI developing after a diagnosis of diabetes.

Congenital pancreatic hypoplasia

This is much less common, but cases have been described in puppies, some of which have concurrent endocrine and exocrine failure, with both EPI and diabetes mellitus. However, some cases of PAA can occur at a very early age 3, making it impossible to evaluate the cause without a pancreatic biopsy.

Pancreatic neoplasia

This is a very rare cause of EPI in small animals.

Clinical presentation

As noted above, EPI can occur in many different breeds of dogs but is more frequently seen in certain breeds including the German Shepherd, the Rough Collie, the Chow Chow, the Cavalier King Charles Spaniel, the West Highland White Terrier, and the Cocker Spaniel 4. For breeds where PAA is the cause, clinical signs usually appear in young adults (before 4 years of age), although in some cases the disease may develop at a later stage. However, when the cause is chronic pancreatitis the age at presentation is typically older, at around 7 years. In some breeds, such as the German Shepherd, the Chow Chow, and the Cavalier King Charles Spaniel, a female gender predisposition has been noted 4.

The most characteristic clinical signs are increased stool frequency and volume, which tends to be yellowish and greasy (steatorrhea), along with weight loss and flatulence (Figure 1). Affected dogs also tend to have decreased stool consistency (i.e., small intestinal diarrhea (Table 1)), polyphagia and coprophagia. Some patients may have episodes of abdominal pain, which can manifest as periods of aggression. Affected dogs generally have a poor body and coat condition (Figure 2), often with seborrhea (Figure 3). Atypically, some dogs may occasionally vomit.

It should be noted that although diarrhea, polyphagia and weight loss are the classical signs, not all may be present in all affected dogs. Some studies have reported that 5% of affected dogs did not have diarrhea, 35% had a normal appetite, 12% had a decreased appetite, and 13% had normal or increased weight 5.

For patients with small intestinal diarrhea in which a chronic enteropathy is suspected, it is essential to exclude the presence of EPI, which is one of the main differential diagnoses (Box 1). EPI is the most frequent extra-gastrointestinal cause of chronic diarrhea in dogs 6.

Diagnosis 

EPI is a functional diagnosis, based on detecting a decrease in secretory capacity via pancreatic function tests. A pancreatic biopsy is necessary to verify the underlying etiology.

The test of choice is the measurement of serum TLI (trypsin-like immunoreactivity). The pancreas secretes trypsinogen into the intestine where it is transformed into the active enzyme trypsin, a potent digestive protease. In addition, small amounts of trypsin can form within the pancreas. Under normal conditions, some of the trypsinogen enters the bloodstream where it can be detected. Trypsin will only be present in the serum when there is pancreatic inflammation. Trypsinogen and plasma trypsin are broken down in the kidneys and by the mononuclear phagocytic system. The TLI test is an immunoassay that detects trypsinogen, trypsin, and trypsin bound to protease inhibitors 7.

The test is a specific, and species-specific, measurement of pancreatic function, and therefore the definitive technique for the canine species (cTLI) must be used. Levels increase in the postprandial period, so the patient should be fasted for 12 hours before sampling. Some authors have recommended suspending the administration of pancreatic enzymes at least one week before any measurement, on the assumption that it could give erroneous TLI levels. However, several studies have indicated that pancreatic enzyme supplementation does not influence TLI measurement in either healthy animals 8 or in dogs with EPI 9, so it is unnecessary to suspend treatment when dealing with a patient for which a definitive diagnosis is required but which has already been given pancreatic enzymes.

In general, when interpreting the cTLI results (Box 2), values lower than 2.5 mg/L are regarded as confirming the presence of EPI. If equivocal results are obtained (between 2.5-5.7 mg/L), the test should be repeated a month later, since not all dogs in this category will progress to having low TLI levels. Such cases, especially if a breed predisposed to PAA, may be in the subclinical phase where there is still adequate secretory function, and which have not yet progressed towards total pancreatic atrophy when clinical signs become apparent 1.

TLI may be increased in patients with pancreatitis, although it is not a reliable diagnostic test, since it only remains elevated for 24-36 hours after the initial insult; the presence of pancreatitis should be confirmed with other tests. TLI may also be elevated for other reasons; these can include some individuals with intestinal disease, as reported in people and cats with various gastrointestinal disorders 10 11 12. Some authors also suggest that small amounts of trypsin can be synthesized in the intestine 10 and in humans, trypsin is present in the small intestine, in the biliary epithelium, and in some ovarian and hepatobiliary neoplasms 7.

In general, a normal TLI result rules out the presence of EPI. Rarely, the TLI result may be normal despite the existence of EPI, for example with a pancreatic duct obstruction 13 or if the patient has a standalone pancreatic lipase deficiency 14.

The interpretation of TLI in dogs with EPI caused by chronic pancreatitis may be more complicated. If the patient has episodes of acute pancreatitis (with digestive signs, anorexia, abdominal pain, etc.), measuring the minimum level of TLI one week after an episode – once the patient is stabilized – is recommended to diagnose EPI. Even so, for dogs with chronic pancreatitis and weight loss where there is no other valid explanation, especially if they have repeatedly borderline TLI values, a therapeutic trial with pancreatic enzymes is recommended.

Other laboratory tests are less useful for diagnosing EPI. PLI is decreased in almost all patients with EPI but there is an overlap of values between affected and healthy patients; however, a specific canine pancreatic lipase test (cPLI) may be helpful in the case of isolated pancreatic lipase deficiency 14. Tests to assess fecal proteolytic activity are not recommended, due to their low sensitivity and specificity. The pancreatic elastase test is widely used in humans to evaluate exocrine pancreatic function, but in dogs it is very non-specific; high values rule out EPI, but low values do not confirm it 1 13.

Serum cobalamin should be measured in all dogs with EPI and is usually decreased in most patients. It is an important prognostic factor 15 and it impacts treatment, as dogs with low levels must receive cobalamin supplementation.

Treatment

Therapy for patients with EPI should primarily include administration of pancreatic enzymes, dietary recommendations, and vitamin B₁₂ or cyanocobalamin supplements.

Pancreatic enzyme supplementation

These can be administered as powder or granules, capsules or coated tablets (to protect the enzymes from gastric acid); some clinicians will also suggest feeding raw pancreas, but this raises the possibility of infectious disease transmission. Some reports have indicated greater efficacy with the use of uncoated forms of supplement, but recent studies have demonstrated the efficacy of coated supplements 9 16. Pancreatic enzymes should be administered along with food (and if using granules, by mixing them with the food just before eating). Pre-incubation of enzymes before administration does not increase the efficacy of the product 13. The dose should be adjusted according to the patient’s needs (i.e., depending on the clinical signs), although digestive capacity generally does not fully recover, even for correctly supplemented patients 1. The side effects of pancreatic enzymes are minimal, although oral bleeding has been described in dogs given high doses; this was controlled by reducing the dose 1.

Diet

The absorption of fat does not completely normalize with pancreatic enzyme supplementation. However, even though low-fat diets were once the norm for dogs with EPI, this can be counterproductive for very thin dogs because the calorie content is quite restricted and this does not help them gain weight. Diets high in fiber should also be avoided, as this alters the activity of pancreatic enzymes and may decrease the assimilation of other nutrients 17. In general, highly digestible, moderate-fat, low-fiber diets are recommended. Some dogs respond well to maintenance diets. However, several studies have not shown clear benefits when comparing specific diets, and individual animals will respond differently to different types of diets. On a practical level, dietary trials should be carried out on each dog to see which is the most effective 17 18.

Cobalamin supplementation

Hypocobalaminemia is very common in animals with EPI and can develop even in dogs already on treatment with pancreatic enzyme supplements. It is therefore essential to monitor cobalamin levels; several studies indicate the negative prognostic factor of hypocobalaminemia in patients with EPI, with a major impact on long-term survival 5 15. All patients with low levels should be supplemented with cobalamin. Historically this has been by subcutaneous injection, but recent studies indicate that it is probably effective to use a daily oral supplement (Box 3) 19.

Antibiotics

There is no good evidence that dogs with EPI improve with antibiotics. They often have bacterial overgrowth or dysbiosis of the intestinal flora, but this tends to be sub-clinical. However, if there is an incomplete response to enzyme supplementation and dietary modification, antibiotics such as ampicillin, metronidazole, or tylosin may be prescribed 17. Since dogs with EPI may have dysbiosis, probiotics could also be considered. Several studies indicate that probiotics may have a potential role in reducing intestinal inflammation and regulating intestinal dysbiosis, and encourage the use of therapies with a good risk/benefit profile (especially taking into account the emergence of bacterial resistance from antibiotic use) 20. However, further study is needed to confirm the efficacy and indications for probiotics in patients with EPI. In addition, it should be remembered that there may be a concurrent enteropathy, so if there is no adequate response to enzyme supplementation and supportive treatment, it would be appropriate to continue with a diagnostic protocol for chronic enteropathies (Box 1).

Antacids

In theory, antacids can be used to decrease gastric hydrolysis of supplemented pancreatic enzymes, but their efficacy has not been proven and it is probably better to increase the dose of the enzyme supplement if necessary. It has been shown that antacids reduce the destruction of lipase, although this does not translate into a clinical benefit 17.

Glucocorticoids

The use of glucocorticoids may be justified in patients with a concurrent chronic enteropathy (e.g., inflammatory bowel disease) or in cases of chronic pancreatitis in breeds such as the English Cocker Spaniel, where there is evidence of an immune-mediated etiology 21. As noted above, further diagnostic tests may be needed for some patients to detect other concomitant problems that may require different treatment, and administration of glucocorticoids may be appropriate in certain cases. Any efficacy and benefit of using immunosuppressants such as azathioprine in the subclinical phase of EPI has not been proven, and is not recommended.

Prognosis

Several studies indicate that ~60% of EPI patients respond well to treatment, 17% have a partial response, and 23% have a poor response, leading to euthanasia in some cases 5. In general, a positive initial response is related to longer-term survival 5. For cases with an underlying chronic pancreatitis, it is important to monitor for other possible concomitant problems such as the presence of diabetes mellitus. Hypocobalaminemia at diagnosis, especially if not accompanied by high levels of folate, is a poor prognostic sign 15.

In all events, pancreatic acinar atrophy is an irreversible process requiring lifelong treatment. Appropriate communication with owners is important; if they are willing to accept the necessary financial implications and be involved in the management and treatment of the disease, the prognosis is generally good, with improvement in the clinical picture at a minimum for most patients.

EPI is a debilitating disease that results from pancreatic acinar tissue atrophy or destruction following chronic pancreatitis. EPI should be ruled out in all patients with suspected chronic enteropathy and suggestive clinical signs (such as weight loss, polyphagia, and diarrhea) and in dogs with chronic pancreatitis and unexplained weight loss for other reasons. The supplementation of pancreatic enzymes and cobalamin, along with the administration of a suitable diet, are fundamental pillars in treating affected dogs.