Introduction
Exocrine Pancreatic Insufficiency (EPI) is a syndrome that is caused by the insufficient production of digestive enzymes by the pancreas. It can be congenital, inherited or acquired leading to loss of weight, polyphagia (excessive hunger or increased appetite), bulky faeces or diarrhoea and occasional vomiting. These signs are attributable to maldigestion and malabsorption of nutrients after approximately 90% of the secretory capacity of the exocrine pancreas has been lost. The ages that are predisposed to this condition range between 1-4 years for congenital cases and between 4-8 years for acquired cases. The breeds that are commonly affected with this syndrome are German Shepherd Dogs (42%), Rough-coated Collies, Eurasians and English Setters for inherited cases while any medium to large breed of dog can acquire the disease. No sex predilection has been observed.
Anatomy of the Pancreas
The pancreas consists of endocrine cells localized within structures named the Islets of Langerhans, which contain multiple endocrine cell types including the β cells that secrete insulin, and the exocrine pancreas, which is composed of acinar cells and ductal structures. Pancreatic acinar cells form a basic structure called an acinus that surrounds a central lumen open to the duct system. Pancreatic acinar cells produce, store and secrete enzymes necessary for the digestion and absorption of food in the small intestine. Digestive enzymes are secreted through the apical membrane of the acinar cell into small intercalated ducts that are directly connected to increasingly larger intralobular ducts that join the main pancreatic duct. The main pancreatic duct joins the common bile duct just prior to the ampulla of Vater, where both pancreatic and liver products enter the small intestine. Blockage of the passage of materials through the ampulla of Vater, for example by the lodging of a bile stone or by the growth of a tumour, leads to increased pressure in the duct system and gives rise to acute pancreatitis.
Aetiology and Pathophysiology of Exocrine Pancreatic Insufficiency
Exocrine Pancreatic Insufficiency (EPI) is caused by idiopathic pancreatic acinar-tissue atrophy (PAA) in a majority of cases (~ 50%, age of onset usually <1-2 years), though there is a suggestion of an autosomal-recessive trait for PAA in German shepherds. Recent studies have however shown that this condition is not caused by a simple autosomal recessive trait. This condition can also be a consequence of chronic pancreatitis in older dogs (>4 years of age). In very rare instances, this condition can be associated with diabetes mellitus in congenital pancreatic hypoplasia.
Progressive pancreatic acinar atrophy leads to lack of pancreatic digestive enzymes in the small intestinal lumen causing impaired nutrient absorption and transport resulting in polyphagia, profound weight loss and loose voluminous stools. Atrophy of the acinar cells is preceded by the accumulation of lymphocytes, and acinar apoptosis (in GSD). Gastrointestinal mucosal trophic factors, regulatory peptides and intrinsic factors are also deficient in pancreatic secretions in this syndrome, leading to changes in small intestinal mucosal function and microanatomy. No evidence of specific anti-pancreatic antibodies in circulation has been observed. in some instances, there is the destruction of pancreatic enzymes in the intestines e.g. in gastric hypersecretion. There is also possible small intestinal bacterial overgrowth due to undigested luminal foodstuff that may alter the intestinal microbiota causing dysbiosis. Other causes include malabsorption of vitamin B12, vitamin E, and rarely vitamin K. Generalized malnutrition might further affect the GI mucosa while the loss of islet cells has been reported to cause diabetes mellitus in patients with EPI secondary to chronic pancreatitis but does not occur in patients with PAA.
Client history
The client presents a dog with a history of weight loss despite a normal or increased appetite (polyphagia). There is also foul-smelling, loose, bulky faeces (stools). The increased faecal volume has a cow patty–like consistency. The number of defecations is also Increased (usually >3/day).
Coprophagia or even pica, flatulence, and borborygmus are also reported with a previous history of acute vomiting (rare), abdominal pain, diarrhoea associated with the acquired disease - pancreatitis. Polydipsia or polyuria in patients with concurrent diabetes mellitus is also noted including instances of nervousness and aggression (rare).
Clinical signs
Physical examination shows a poor body condition, muscle wasting, poor hair quality (hair coat), polyphagia, bulky faeces and or diarrhoea. Coprophagia is common and helps to differentiate it from IBD [Inflammatory bowel disease].
Diagnosis
History
Clinical signs
Biochemistry
Canine trypsin-like immunoreactivity (cTLI) This species-specific test is used to quantify trypsinogen and trypsin in serum. A cTLI concentration < 2.5 mcg/L after withholding food for > 8 hours is considered confirmatory. A serum cTLI concentration between 2.5 and 5.7 mcg/L may be associated with occult EPI. Serum cTLI should be retested in 1 to 2 months. Decreased cTLI concentration is highly sensitive and specific for EPI and is not affected by enzyme supplementation. Low serum - trypsin-like immunoreactivity. Rule out acute pancreatitis (raised ALT, reduced cholesterol).
Low serum cobalamin [Blood biochemistry: vitamin B12] +/- high folate.
Non-specific alterations suggestive of malnutrition:
Hypoproteinemia - very rare.
Faecal elastase concentration This enzyme-linked immunosorbent assay has high sensitivity but low specificity. Faecal elastase concentration is a new test validated in dogs. Low faecal elastase is indicative of EPI. However, there is a high false-positive rate (23%). Diagnosis should always be confirmed by cTLI. A value > 20 mcg/g helps to eliminate EPI. Values < 10 mcg/g will require confirmation with cTLI. Faecal analysis for proteolytic activity commonly used to diagnose exocrine pancreatic insufficiency is EXTREMELY misleading with false positive and false negative results - with highly sensitive and specific TLI assay available no reason to do faecal analysis.
Gross autopsy findings
Pancreatic atrophy.
Histopathology findings
Pancreatic acinar atrophy.
Fibrotic change associated with chronic inflammation.
Differential diagnosis
Weight loss and diarrhoea
Inflammatory bowel disease.
Intestinal neoplasia.
Renal failure [Kidney: chronic kidney disease (CKD)].
Neoplasia of other systems.
Parasites of the gastrointestinal tract, eg Giardia.
Metabolic/endocrine disease.
Toxaemia/sepsis [Shock: septic].
Poor diet.
Hepatic failure [Liver: acute disease].
Lymphocytic plasmacytic enteritis.
Eosinophilic enteritis.
Lymphangiectasia [Protein-losing enteropathy].
Small intestinal bacterial overgrowth [Antibiotic-responsive diarrhoea] , stagnant loop syndrome/antibiotic responsive enteropathy.
Drug therapy.
Gluten-sensitive enteropathy.
Primary or secondary causes of chronic small-bowel diarrhoea
Disorders associated with weight loss (eg, systemic conditions, diabetes mellitus, hepatic failure, malignancies, and many others)
Polyphagia
Hyperadrenocorticism [Hypoadrenocorticism].
Hyperthyroidism due to functional neoplasm.
Treatment
Standard treatment
Pancreatic enzyme replacement.
Highly digestible, +/- fat-restricted ;15% Diabetes Mellitus diet.
Medium-chain triglyceride [Fat] supplementation may be given with care.
Cobalamin/vitamin B12 supplementation (1mg SQ, q1month) (parenteral NOT oral).
Vitamin E/vitamin K supplements if needed.
Monitoring
Improvements will be noticed in the following order:
Normal faeces passed (48-72 h).
Weight gain (over weeks).
Polyphagia reduces (reduces once weight restored).
Subsequent management
If basic treatment regime failing, course of antibiotic (oxytetracycline 28d PO) indicated for bacterial overgrowth /antibiotic responsive enteropathy.
Further evaluation for concurrent small intestinal disease.
If poor response, try H-2 antagonists prior to feeding to protect enzyme replacer against gastric acid [Cimetidine].
Patient Monitoring
Regular weight checks.
Rapid weight gain is expected, but bodyweight may fail to normalize despite remission of clinical signs.
Diarrhoea resolves in 2 to 7 days in uncomplicated cases.
EPI Patient before treatment
The Patient after treatment of EPI
Complications
Food aversion may result from enzyme addition (rare in dogs).
Approximately 20% of dogs do not respond to initial enzyme replacement.
Concurrent cobalamin deficiency, small intestinal dysbiosis, inflammatory bowel disease, diabetes mellitus, or other conditions may need to be addressed.
Prognosis
This is a lifelong condition in almost all patients.
Anecdotal recovery from EPI has been reported.
Prognosis is favourable, and response to long-term enzyme therapy is good after stabilization.
Occasional short relapses can occur.
Prevention
A patient with EPI due to PAA should not be bred.
Future Considerations
Little is known about the pathogenesis and progression of subclinical to clinical EPI. Studies directed at this might help prevent progression of the disease during the subclinical phase.
Dogs can lead a normal life and can have a normal life expectancy.
Some dogs do not adequately respond to therapy.
Concurrent cobalamin deficiency has been associated with a poor outcome and must be treated.
References
Westermarck E & Wiberg M E (2006) Effects of diet on clinical signs of exocrine pancreatic insufficiency in dogs. JAVMA 228 (2), 225-229 PubMed.
A survey of the diagnosis and treatment of canine exocrine pancreatic insufficiency. Hall EJ, Bond PM, McLean C, et al. J Small Anim Pract 32:613-619, 1991.
Wiberg M E, Saari S A, Westermarck E & Meri S (2000) Cellular and humoral immune responses in atrophic lymphocytic pancreatitis in German Sheperd dogs and Rough-coated Collies. Vet Immunol Immunopathol 76 (1-2), 103-115
Simpson J W & Else R W (1991) Diseases of the exocrine pancreas. In: Digestive Disease in the Dog and Cat. pp 198-303. Oxford. Blackwell Scientific Publications. (Good synopsis of disease.)
Oral bleeding associated with pancreatic enzyme supplementation in three dogs with exocrine pancreatic insufficiency. Rutz GM, Steiner JM, Williams DA. JAVMA 221:1716-1718, 2002.
Sensitivity and specificity of radioimmunoassay of serum trypsin-like immunoreactivity for the diagnosis of canine exocrine pancreatic insufficiency. Williams DA, Batt RM. JAVMA 192:195-220, 1988.
Simpson et al(1994) Long-term management of canine exocrine pancreatic insufficiency. JSAP 35 , 133-138.
Williams D & Batt R M (1983) Diagnosis of EPI by assay of serum TLI. JSAP 24 , 583-588.
Exocrine pancreas. Steiner JM. In Steiner JM (ed): Small Animal Gastroenterology—Hannover, Germany: Schlütersche, 2008, pp 294-299.
The role of protein synthesis and digestive enzymes in acinar cell injury. Craig D. Logsdon & Baoan Ji Nature Reviews Gastroenterology & Hepatology 10, 362-370 (June 2013) doi:10.1038/nrgastro.2013.36
Mesenteric torsion in dogs with exocrine pancreatic insufficiency: 21 cases (1978-1987). Westermarck E, Rimaila-Pärnänen E. JAVMA 195:1404-1406, 1989.
Prognostic factors in canine exocrine pancreatic insufficiency: Prolonged survival is likely if clinical remission is achieved. Batchelor DJ, Noble PM, Cripps PJ, et al. J Vet Intern Med 21:54-60, 2007.
Heritability of exocrine pancreatic insufficiency in German shepherd dogs. Westermarck E, Saari SA, Wiberg ME. J Vet Intern Med 24:450-452, 2010.
Exocrine pancreatic insufficiency. Wiberg M. In Bonagura JD, Twedt DC (eds): Kirk’s Current Veterinary Therapy, IV—St. Louis, Saunders Elsevier, 2009, pp 531-534.