Redefining Chronic Pancreatitis
World Small Animal Veterinary Association World Congress Proceedings, 2014
Jörg M. Steiner, DrMedVet, PhD, DACVIM, DECVIM-CA, AGAF
Texas A&M University, College Station, TX, USA

Introduction

Pancreatitis, an inflammatory condition of the pancreas can either be acute or chronic. However, acute and chronic pancreatitis cannot be differentiated based on clinical evaluation alone, but only based on histopathologic evaluation. Chronic pancreatitis is characterized by an inflammatory infiltration of the exocrine pancreas that is associated with permanent changes, mainly pancreatic fibrosis and/or pancreatic atrophy, while such changes cannot be identified in patients with acute pancreatitis. Both acute and chronic pancreatitis are associated with inflammatory infiltration. In patients with acute pancreatitis, neutrophils and macrophages often represent the predominant cell type, while the inflammation in patients with chronic pancreatitis is often lymphocytic and/or plasmacytic. Both acute and chronic pancreatitis can also be associated with varying degrees of pancreatic necrosis and peripancreatic fat necrosis. Also, clinically, both acute and chronic pancreatitis can range from a subclinical disease to severe disease, associated with systemic and pancreatic complications. However, it should be noted that chronic pancreatitis is less often associated with clinical signs of severe disease.

Historically, canine pancreatitis was believed to be acute in the majority of cases and feline pancreatitis was believed to be chronic. However, in a large necropsy study conducted in dogs at the Animal Medical Center in New York, histopathologic evidence of chronic pancreatic inflammation was observed almost twice as frequently as was evidence of acute pancreatic inflammation.1 As a result, it is now recognized that dogs and cats have chronic pancreatitis with approximately the same ratio - roughly two thirds of pancreatitis cases in both dogs and cats are chronic, while only approximately one third is acute.2

The exact etiology of chronic pancreatitis remains unknown in most cases. However, several risk factors have been identified for pancreatitis in general, and several of those more likely lead to chronic than acute pancreatitis. Similar to humans, there are several breeds that appear overrepresented, mainly Miniature Schnauzers and English Cocker Spaniels.3,4 This would suggest a hereditary component of this disease in some patients. For the Miniature Schnauzer, 3 mutations of the SPINK1 gene (this gene encodes pancreatic secretory trypsin inhibitor, an important inhibitory molecule for prematurely activated trypsin) have been shown to cosegregate with pancreatitis.5 However, a cause and effect relationship for these mutations and pancreatitis has not been demonstrated to date. A similar breed-predisposition has not been proposed for cats, and thus hereditary causes of pancreatitis do not appear to play a role in this species.

Hypercalcemia can also cause pancreatitis, though it is unclear whether most cases of hypercalcemia-induced pancreatitis are acute or chronic. Severe hypertriglyceridemia also is considered to be a risk factor for pancreatitis, with a more than 5-fold increase in the odds ratio for pancreatitis when serum triglyceride concentrations are higher than 850 mg/dL.4 This is similar to the situation in humans where serum triglyceride concentrations above 1000 mg/dL have been associated with a significantly increased risk for pancreatitis. Also, in some patients, hypertriglyceridemia appears to be more a risk factor for acute rather than chronic pancreatitis. Many medications have been associated with an increased risk for pancreatitis, but for most of them, the relationship is not dose-dependent and predictable, but rather appears to be a type of idiosyncratic reaction that then leads to acute pancreatitis. One notable exception are the antiepileptic agents potassium bromide and phenobarbital. In patients treated with either of these drugs, mild and often subclinical pancreatitis can be observed after long periods of therapy.6 However, the notion that therefore pancreatitis is most likely chronic has not been substantiated with histopathologic evaluation of pancreatic biopsy specimens. Wether concurrent inflammatory conditions of abdominal organs, such as the intestines or the liver might be risk factors for chronic pancreatitis, remains unknown. It may be more likely that both chronic pancreatitis and these inflammatory conditions of other abdominal organs have the same etiopathogenesis rather than cause each other.7 Interestingly, many cases of chronic pancreatitis in dogs and cats are characterized by lymphocytic and plasmacytic infiltration, a pattern that is also often seen in intestinal and/or hepatic biopsies in dogs and cats with IBD and/or hepatitis/cholangitis.8 Humans with autoimmune pancreatitis also show inflammatory infiltration of the pancreas with lymphocytes and plasma cells. While the overall pathologic and histopathologic appearance of the pancreas in humans with autoimmune pancreatitis on one side and dogs and cats with chronic pancreatitis on the other are not the same, an immune-mediated etiology in some of these patients is a very attractive possibility, especially as it relates to therapeutic implications of such a relationship. In humans, one of the features of autoimmune pancreatitis is response to steroid therapy, which has also been shown to be beneficial in some canine and feline patients with chronic pancreatitis (more below). Also, many patients with autoimmune pancreatitis are associated with IgG4-positive lymphocytes, which has also been observed in some dogs.

Clinical Presentation

As indicated above, both acute and chronic pancreatitis can cause disease of varying degrees of severity, but chronic pancreatitis is more commonly mild than severe, which makes diagnosis a lot more challenging. Interestingly, only few reports specifically describe the clinical characteristics of dogs or cats with chronic pancreatitis.8,9 Ultimately, clinical signs of chronic pancreatitis are usually nonspecific and mild, including lethargy, anorexia, and in some cases loose stools.8 In more severe cases, vomiting and abdominal discomfort may be observed, but these signs are not very consistent and are less frequent in cats than they are in dogs. Thus, it is important to consider chronic pancreatitis as a rule out in dogs and cats with nonspecific clinical signs.

Chronic pancreatitis is often associated with other inflammatory conditions of abdominal organs, most notably the intestinal tract (i.e., inflammatory bowel disease), the liver (i.e., chronic hepatitis in dogs and chronic cholangitis in cats), or even the kidneys (i.e., nephritis).7 These concurrent conditions can be associated with additional clinical signs, which however, in many cases overlap with the clinical signs of chronic pancreatitis itself. Diabetes mellitus is also a common concurrent condition in dogs and cats with chronic pancreatitis and is associated with PU/PD. There is no definitive evidence that the chronic inflammation of the pancreas leads to destruction of both acinar cells and islet cells of Langerhans, but this pathogenetic mechanism is rational and has been proposed for many years.

Diagnosis

Chronic pancreatitis should be considered as a potential differential diagnosis in any dog or cat with chronic gastrointestinal signs (i.e., anorexia, loose stools, weight loss, vomiting, or other), where another underlying cause cannot be readily identified. A careful history should be taken and a thorough physical examination should be completed. Then the patient should be evaluated for endoparasites by a routine fecal smear, fecal floatation, and a therapeutic trial with a broad-spectrum anthelminthic agent. Next, the patient should be evaluated for secondary causes of gastrointestinal disease by performing a complete blood count, a serum chemistry profile, and a urinalysis. If no abnormalities are found that identify a definitive secondary cause for the chronic gastrointestinal signs, the patient should be evaluated for exocrine pancreatic insufficiency (unless the patient does not have loose stools nor weight loss) by measurement of a serum canine trypsin-like immunoreactivity concentration (cTLI or fTLI) and for chronic pancreatitis by measurement of a serum pancreatic lipase immunoreactivity concentration (cPLI and fPLI, now measured by Spec cPL® and Spec fPL®).

Many different cell types in the body synthesize and secrete lipases. In contrast to catalytic assays for the measurement of lipase activity, use of immunoassays does allow for the specific measurement of lipase originated from the exocrine pancreas. Serum cPLI was measured in a group of dogs with exocrine pancreatic insufficiency, and the median serum cPLI concentration was significantly decreased compared to clinically healthy dogs.10 In addition, serum cPLI concentration was nondetectable in most of the dogs, and minimal serum cPLI concentrations were observed in the rest of the dogs, indicating that serum cPLI concentration originates from the exocrine pancreas and is specific for exocrine pancreatic function. In another study, serum cPLI was evaluated in dogs with experimentally induced chronic renal failure. While serum cPLI was significantly higher in dogs with experimentally induced chronic renal failure than in clinically healthy dogs, most dogs had serum cPLI concentrations within the reference range, and none of the dogs had serum cPLI concentrations that were above the currently recommended cut-off value for pancreatitis. Also, long-term oral administration of prednisone did not have any effect on serum cPLI concentration. In another study, the specificity of cPLI in healthy dogs was shown to be 97.5%.11 These data would suggest that serum cPLI concentration is highly specific for pancreatitis in dogs. Finally, the sensitivity of different minimally invasive diagnostic tests was compared in dogs with pancreatitis. The sensitivity of serum TLI concentration was below 35% and that of serum lipase activity was less than 55%. In contrast, the sensitivity for serum cPLI concentration for pancreatitis was above 80%. Several other studies have shown similar results for both dogs and cats. There is no doubt that sensitivity does decrease as the severity of disease decreases. In a recent study the sensitivity of Spec cPL for mild pancreatitis was described as only 21%, but was 71% for moderate-to-severe pancreatitis. However, interestingly, the specificity was high at 100%, which was not the case for other minimally invasive tests, such as serum lipase activity (specificity 43%).12 In another study of subclinical and mild pancreatitis in dogs, the sensitivity or the assay was approximately 65%, far greater than any of the other minimally invasive tests.13 Thus, while the sensitivity of the measurement of serum PLI (Spec cPL and Spec fPL) does decrease for less severe disease, measurement of PLI concentration remains extremely specific and more sensitive than any other diagnostic test for pancreatitis available for both dogs and cats. It should also be noted that abdominal ultrasound is not very sensitive for chronic pancreatitis. While a systematic study that evaluates the sensitivity of abdominal ultrasound in dogs and cats with chronic pancreatitis is not available, anecdotal reports and clinical experience would suggest that findings in patients with mild or subclinical disease can often not be reliably identified on abdominal ultrasound. Thus, a diagnosis of chronic pancreatitis in dogs and cats rests on a combination of clinical signs, exclusion of diseases that could cause similar clinical signs, findings on abdominal ultrasound if present and convincing, and an increased serum Spec cPL or Spec fPL concentration.

Therapy

As mentioned above, often times patients with chronic pancreatitis have concurrent conditions, most notably IBD. Very little is known about appropriate therapy for these patients, and management is often limited to evaluation and treatment of the concurrent condition, and careful monitoring of the pancreatitis. Serum calcium and triglyceride concentrations should always be evaluated in these patients in order to identify any risk factors that can potentially be addressed therapeutically. Also, the use of an ultra-low-fat diet is recommended in dogs with chronic pancreatitis. In cats with chronic pancreatitis, a moderately fat-restricted diet should be chosen, as the impact of dietary fat appears to be less in cats than in dogs. Patients should be monitored for a decrease in serum PLI concentration, initially every 2–3 weeks, and less frequently as the condition improves.

Over the last two decades, a new form of pancreatitis - autoimmune pancreatitis - has been described in humans. As mentioned above, human patients with autoimmune pancreatitis respond favourably to the administration of corticosteroids or other immunosuppressive drugs. Several veterinary clinicians have started to cautiously treat canine and feline patients with chronic pancreatitis with corticosteroids and have found this treatment strategy to be beneficial in a portion of cases, but further research is needed before this treatment strategy can be recommended for routine use. There may be uneasiness in treating patients with chronic pancreatitis with corticosteroids, as many of these patients are glucose intolerant or may even have frank diabetes mellitus. However, studies in humans have shown that patients with autoimmune pancreatitis show an overall improved control of diabetes mellitus after treatment with glucocorticoids, even though less than 20% of patients develop diabetes mellitus after glucocorticoid therapy has been initiated. Also, a few dogs and cats with chronic pancreatitis have been successfully treated with cyclosporine.14 Cyclosporine has the theoretical advantage that it is has a less significant impact on insulin resistance than do glucocorticoids.

References

1.  Newman S, Steiner J, Woosley K, Barton L, Ruaux C, Williams D. Localization of pancreatic inflammation and necrosis in dogs. J Vet Int Med. 2004;18(4):488–493.

2.  DeCock HEV, Forman MA, Farver TB, Marks SL. Prevalence and histopathologic characteristics of pancreatitis in cats. Vet Pathol. 2007;44(1):39–49.

3.  Watson PJ, Roulois A, Scase T, Holloway A, Herrtage ME. Characterization of chronic pancreatitis in English Cocker spaniels. J Vet Intern Med. 2011;25:797–804.

4.  Xenoulis PG, Suchodolski JS, Ruaux CG, Steiner JM. Association between serum triglyceride and canine pancreatic lipase immunoreactivity concentrations in miniature schnauzers. J Am Anim Hosp Assoc. 2010;46(4):229–234.

5.  Bishop MA, Xenoulis PG, Levinski MD, Suchodolski JS, Steiner JM. Identification of variants of the SPINK1 gene and their association with pancreatitis in Miniature Schnauzers. Am J Vet Res. 2010;71(5):527–533.

6.  Steiner JM, Xenoulis PG, Anderson JA, Barr AC, Williams DA. Serum pancreatic lipase immunoreactivity concentrations in dogs treated with potassium bromide and/or phenobarbital. Vet Ther. 2008;9(1):37–44.

7.  Weiss DJ, Gagne JM, Armstrong PJ. Relationship between inflammatory hepatic disease and inflammatory bowel disease, pancreatitis, and nephritis in cats. J Am Vet Med Assoc. 1996;209(6):1114–1116.

8.  Bostrom BM, Xenoulis PG, Newman SJ, Pool RR, Fosgate GT, Steiner JM. Chronic pancreatitis in dogs: a retrospective study of clinical, clinicopathological, and histopathological findings in 61 cases. Vet J. 2013;195(1):73–79.

9.  Watson PJ, Archer J, Roulois AJ, Scase TJ, Herrtage ME. Observational study of 14 cases of chronic pancreatitis in dogs. Vet Rec. 2010;167(25):968–976.

10. Steiner JM, Rutz GM, Williams DA. Serum lipase activities and pancreatic lipase immunoreactivity concentrations in dogs with exocrine pancreatic insufficiency. Am J Vet Res. 2006;67(1):84–87.

11. Neilson-Carley SC, Robertson JE, Newman SJ, Kutchmarick D, Relford R, Woosley K, et al. Specificity of a canine pancreas-specific lipase assay for diagnosing pancreatitis in dogs without clinical or histologic evidence of the disease. Am J Vet Res. 2011;72(3):302–307.

12. Trivedi S, Marks SL, Kass PH, Luff JA, Keller SM, Johnson EG, et al. Sensitivity and specificity of canine pancreas-specific lipase (cPL) and other markers for pancreatitis in 70 dogs with and without histopathologic evidence of pancreatitis. J Vet Intern Med. 2011;25:1241–1247.

13. Steiner J, Newman S, Xenoulis P, Woosley K, Suchodolski J, Williams D, et al. Sensitivity of serum markers for pancreatitis in dogs with macroscopic evidence of pancreatitis. Vet Ther. 2008;9(4):263–273.

14. Steiner JM, Huber BJ. Management of a dog with poorly regulated diabetes mellitus, chronic pancreatitis, and suspected atopy with cyclosporine. Case Rep Vet Med. 2012; doi:10.1155/2012/510639.

  

Speaker Information
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Jörg M. Steiner, DrMedVet, PhD, DACVIM, DECVIM-CA, AGAF
Texas A&M University
College Station, TX, USA


MAIN : GI - Pancreas and Liver : Chronic Pancreatitis
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