Acute Pancreatitis

2. Acute Pancreatitis: Diagnostic

Diagnostic Reminder

A diagnosis of acute pancreatitis is based on a combination of compatible clinical, clinicopathological and imaging findings. Surgical biopsy may be required to confirm a diagnosis, and to distinguish inflammation from neoplasia.

History

The history may reveal a recent episode of dietary indiscretion, toxin ingestion (e.g., chocolate or high-fat food) or drug administration. Common clinical signs include lethargy, anorexia, hunched stance, vomiting (± blood), diarrhea (± blood), increased respiratory rate and enlarged abdomen. Some dogs have a history of icterus preceded by vomiting.

Polyuria and polydipsia may be present in dogs with diabetes mellitus and pancreatitis.

Physical Examination

Physical findings in dogs with acute pancreatitis are very variable, ranging from depression, to mild dehydration with signs of abdominal pain, to acute abdominal crisis, shock (tachycardia, prolonged capillary refill time, tacky mucous membranes, hypothermia), petechiation, icterus and ascites. An abdominal mass is palpated in some dogs.

Dog suffering from acute pancreatitis. (©KW Simpson).

Supplementary Tests - Clinicopathological Findings

Hematology

Extremely variable, ranging from mild neutrophilia and slightly increased hematocrit, through marked leukocytosis with or without a left shift, to thrombocytopenia, anemia and neutropenia with a degenerative left shift. When thrombocytopenia is detected, tests of hemostasis (OSPT, APTT, FDP or D-dimer, fibrinogen, antithrombin III) are performed to determine if the patient has a disseminated intravascular coagulopathy (DIC).

Serum Biochemistry

Serum biochemical abnormalities include azotemia (pre-renal and renal), increased liver enzymes (ALT, AST, AP), hyperbilirubinemia, lipemia, hyperglycemia, hypoproteinemia, hypocalcemia, metabolic acidosis and variable abnormalities (usually decreased) in sodium, potassium and chloride.

Urinalysis

Urinalysis enables azotemia to be characterized as renal or pre-renal. Proteinuria occurs in some dogs with acute pancreatitis, possibly as a consequence of pancreatic enzyme-mediated glomerular damage, and is usually transient. The presence of glucose or ketonuria should prompt consideration of diabetes mellitus.

Pancreas Specific Enzymes

Classically, elevations in serum amylase and lipase activity have been used as indicators of pancreatic inflammation in dogs. However these enzymes can be increased in non-pancreatic disease, and dogs with confirmed pancreatitis may also have normal amylase and lipase activity. For example, in dogs with histologically confirmed pancreatitis, lipase is normal in 28 to 61% of dogs, and amylase is normal in 31 to 47% of dogs (Strombeck et al., 1981; Hess et al., 1998; Mansfield et al., 2003). These limitations have led to the development of assays for enzymes or markers considered pancreatic in origin such as trypsin-like immunoreactivity (TLI), trypsinogen activation peptide (TAP), and pancreatic lipase immunoreactivity (PLI). Experimental studies have documented high concentrations of TLI, TAP and PLI in dogs with experimental acute pancreatitis.

The utility of TLI, TAP and PLI for the diagnosis of spontaneous pancreatitis in dogs has not been thoroughly evaluated. Normal, subnormal and increased concentrations of TLI have been observed in dogs with confirmed pancreatitis and TLI level does not predict severity (Ruaux & Atwell, 1999). Elevations of TAP have been observed in the serum and urine of dogs with severe pancreatitis, and TAP may be a better prognostic than diagnostic indicator of pancreatic inflammation (Mansfield & Jones, 2000; Mansfield et al., 2003). Experience with PLI is even more limited, though it appears more promising than TLI as serum elevations of PLI seem more substantial and prolonged than TLI. Diseases such as renal disease can increase TLI, TAP and PLI.

Radiography

Radiographic findings in dogs with acute pancreatitis are generally non-specific and include loss of serosal detail, increased opacity in the right cranial quadrant of the abdomen, displacement of the duodenum ventrally and/or to the right, dilated hypomotile duodenum and caudal displacement of the transverse large intestine. Punctate calcification may occasionally be identified in dogs with long-standing pancreatitis. It indicates saponification of mesenteric fat around the pancreas.

Thoracic radiographs may enable the detection of pleural fluid, edema or pneumonia which has been associated with pancreatitis in dogs.

Ultrasonography

One study of dogs with fatal acute pancreatitis indicated that ultrasound supported a diagnosis of pancreatitis in 23/34 dogs (Hess et al.,1998).

Ultrasonographic signs identical to those observed in the case of pancreatitis (Figure 11a and Figure 11b) may exist alongside other disorders such as pancreatic neoplasia, pancreatic edema (associated with hypoproteinemia or portal hypertension) and enlarged peri-pancreatic structures (Lamb et al., 1995). Fine needle aspirates of cavitary lesions may be useful to distinguish abscess from pseudocyst.

Figure 11a. Ultrasonographic findings in a dog. The pancreas is diffusely enlarged with irregular margins and mixed echogenicity. The mesenteric fat in the right cranial abdomen is hyperechoic and scatters sound. (©KW Simpson).

Figure 11b. Ultrasonographic findings in a dog. The duodenum at the cranial flexure has a diameter of 1.6 cm with a thick wall of 6.2 mm. There is a moderate amount of gas in the duodenum and it has a corrugated appearance. Conclusions: suspect pancreatitis, focal peritonitis. (©KW Simpson).

Other Imaging Modalities

Contrast enhanced computed tomography is the imaging technique of choice in people with pancreatitis and enables the distinction between pancreatic necrosis and mild pancreatitis. It has only undergone preliminary evaluation in dogs (Jaeger et al., 2003).

Abdominal Paracentesis

Examination of peritoneal fluid may aid the detection of various causes of acute abdominal signs such as pancreatitis, gastrointestinal perforation or ruptured bile duct.

Surgery

Surgical intervention can be undertaken in patients with persistent or recurrent pancreatitis to confirm the diagnosis and to detect neoplasia and complicating factors such as infection. Surgery is also indicated to drain pancreatic abscesses and persistent pseudocysts (Salisbury et al., 1988). The advent of laparascopic techniques may decrease morbidity (Harmoinen et al., 2002).Surgery is also indicated to place enteral feeding tubes (see Nutritional Management below) and it is prudent to consider feeding tube placement prior to an exploratory surgery in dogs with suspected pancreatitis.

Differential Diagnosis

The differential diagnosis of acute pancreatitis in dogs is usually focused on vomiting and abdominal pain (Table 3). The combined results of the history, physical examination, clinicopathological tests and diagnostic imaging are used to distinguish pancreatitis from metabolic, polysystemic infectious, toxic, neurologic and other intra-abdominal causes of vomiting.

Where abdominal pain is the major finding it is rapidly pursued with radiography, ultrasonography, and paracentesis, with supportive treatment provided on the basis of physical findings and initial clinicopathological testing (Macintire,1988.)

Diarrhea, that can be bloody, may also be observed in dogs with acute pancreatitis. Acute pancreatitis and its complications (infection, pseudocyst or abscess formation) should be considered in the differential diagnosis of icterus and pyrexia.

Pitfalls and Frequent Mistakes

Pancreatitis is likely to be overdiagnosed when either clinical signs or clinicopathological tests are used as the major/sole diagnostic criteria. Acute enteritis, intestinal obstruction and a variety of causes of the acute abdomen can have very similar clinical and clinicopathological findings to those of pancreatitis.

Over-reliance on serum markers of pancreatic disease may lead to misdiagnosis. Increases in total amylase and lipase are commonly encountered in a variety of other conditions, and normal values do not exclude pancreatitis. More specific tests of pancreatic inflammation such as TLI, TAP and PLI have not been thoroughly validated at this point so caution is advised when considering them.

Changes in pancreatic echogenicity and size have to be determined by a qualified sonographer, and the sonographic findings integrated with other findings to determine if pancreatitis is a likely diagnosis. Pancreatitis has to be distinguished from neoplasia, or other causes of parenchymal fluid accumulation such as portal hypertension, or hypoproteinemia.

Epidemiology

Risk Factors

Middle aged to old dogs (>5 years old) that are overweight appear at higher risk. There is no clear sex predisposition. Dietary indiscretion, consumption of high fat meals, and the administration of drugs (e.g., azathioprine, phenobarbital and potassium bromide) or toxins (e.g., organophosphates) have been reported to precede the development of clinical signs suggestive of pancreatitis in dogs (Simpson, 1993; Hess et al., 1999).

Endocrinopathies such as hypothyroidism, diabetes mellitus and hyperadrenocorticism may also be risk factors (Hess et al., 1999). Thirteen percent of 221 dogs with diabetes mellitus had histological evidence of acute pancreatitis. Hyperlipidemia is another potential risk factor (Hess et al., 2000).

Breed Predispositions

Miniature Schnauzers, Yorkshire and Silky Terriers and perhaps miniature Poodles may be at increased risk of developing pancreatitis.

The risk of pancreatitis will be higher in Miniature Schnauzers. (©Hermeline).

Pathophysiological Mechanisms

The etiology and pathogenesis of spontaneous pancreatitis is poorly understood (Karne & Gorelick, 1999; Zyromski & Murr, 2003). A wide variety of factors have been implicated by association or experimentation as causes of acute pancreatitis in the dog. The potential causes of pancreatitis with a nutritional aspect are summarized in Figure 12a and Figure 12b.

Clinically, inflammation of the pancreas can be broadly categorized as acute, recurrent acute, or chronic. Acute and recurrent acute pancreatitis are characterized by sudden episodes of inflammation and appear to be the most frequent form of pancreatitis in the dog.

• Acute pancreatitis may resolve or may cause continued inflammation (chronic or recurrent acute) or necrosis which can be complicated by secondary infection and pseudocyst or abscess formation (Figure 13 & Figure 14).
• Chronic pancreatitis is characterized by low grade or sub-clinical inflammation and may be a factor in the development of diabetes mellitus and exocrine pancreatic insufficiency (EPI) in dogs.

Figure 13. Pancreatic abscess. Pancreatic abscess is a rare complication of acute pancreatitis in the dog. Treatment is generally surgical.

Figure 14. Proposed progression of pancreatitis in dogs (from: Simpson & Lamb, 1995).

Regardless of the initiating cause, pancreatitis is generally considered to occur when digestive enzymes are activated prematurely within the pancreas. Experimental pancreatic hyperstimulation withcholecystokinin (CCK) or its analogue cerulein, dietary supplementation with ethionine, and obstruction of the pancreatic duct lead to the formation of large intracellular vacuoles in acinar cells. Vacuole formation is thought to be a consequence of the uncoupling of exocytosis of zymogens and abnormal intracellular trafficking of digestive and lysosomal enzymes. These subcellular alterations are considered to precipitate the intracellular activation of digestive enzymes.

Pancreatic hyperstimulation may be of direct relevance to naturally occurring pancreatitis in dogs. CCK is normally released by cells in the duodenum in response to intraluminal fat and amino acids and coordinates and stimulates pancreatic secretion and gallbladder contraction during digestion. It is possible that high fat diets exert their effects via the excessive release of cholecystokinin and that hypercalcemia, organophosphates and high levels of circulating glucocorticoids also facilitate (potentially by changing pancreatic sensitivity to hyperstimulation), or cause pancreatic hyperstimulation; however, this is not proven.

Edematous pancreatitis induced by CCK hyperstimulation in dogs is characterized by a rapid but self-limiting, burst of trypsinogen activation (Figure 15a, Figure 15b & Figure 15c), suggesting that the pancreas has a feedback mechanism to limiting trypsinogen synthesis and activation (see Nutritional Management) (Simpson et al., 1995). This concept of pancreatic down regulation is important when considering nutritional intervention in acute pancreatitis.

Figure 15a. Edematous pancreatitis and intrapancreatic activation of trypinogen. Edematous pancreatitis is generally regarded as the mildest form of pancreatitis.

Figure 15b. Edematous pancreatitis and intrapancreatic activation of trypinogen. It is associated with self-limiting trypsinogen activation and release of trypsinogen activation peptide (TAP) into the circulation.  

Figure 15c. Edematous pancreatitis and intrapancreatic activation of trypinogen. In the clinical setting the accumulation of fluid within the pancreas can be detected with ultrasound.  

Release of active pancreatic enzymes and inflammatory mediators from the inflamed pancreas, such as tumor necrosis factor (TNF-α) interleukin-1 (IL-1) and platelet activating factor (PAF), amplify the severity of pancreatic inflammation, and adversely affects the function of many organs (systemic inflammatory response), and cause derangement in fluid, electrolyte and acid-base balance (Denham & Norman, 1999; Ruaux et al., 1999; Brady & Otto, 2001; Mentula et al., 2004 ; Raraty et al., 2004).

Figure 16. Pancreatic necrosis and its consequences.

It is the development of multisystemic abnormalities that separates mild from severe, potentially fatal pancreatitis. Elucidating the systemic inflammatory response holds the promise of novel treatments for acute pancreatitis and is the focus of current research (Johnson et al., 2004; Oruc et al., 2004).

Nutritional Management

Identify and Prevent, or Treat, Nutritional Factors Associated with Pancreatitis

Obesity, hyperlipidemia and dietary indiscretion are reported to be associated with pancreatitis in dogs. Where these are present it would seem prudent to address their underlying cause in an attempt to prevent future bouts of pancreatitis.

Nutrient Provision to Dogs with Pancreatitis

Precise recommendations for the dietary management of acute pancreatitis in dogs are hampered by the absence of controlled studies, and are often based on empirical wisdom and a best guess least harm approach.

The Dilemma Between Feeding and Stimulating the Pancreas

It has been well documented that pancreatic secretion in healthy dogs occurs in response to ingested nutrients, particularly fats and amino acids delivered into the duodenum (Figure 17).

Figure 17. Regulation of pancreatic secretion (from Johnson, 1997). Hormones such as CCK and secretin, the parasympathic system and the nerves of the duodenum and pancreas play a role in the pancreatic secretion in response to the arrival of food.

Restricting oral intake, or providing nutrients intravenously, does not stimulate pancreatic secretion (Stabile et al., 1984). Thus it has been largely accepted that to provide "pancreatic rest" oral intake should be withheld until clinical signs resolve, or when signs persist for approximately 7296 hrs that parenteral nutrition is introduced. This dogma is still prevalent in veterinary and human medicine.

However, there is growing evidence in people and animals that enteral nutrition is superior to parenteral nutrition in the treatment of acute pancreatitis. It has been shown in both people and animals that jejunal feeding (distal to the site of pancreatic stimulation) does not exacerbate acute pancreatitis (Vu et al., 1999; Qin et al., 2002, Qin et al., 2003).

People with acute pancreatitis fed via jejunostomy tubes (these can be oral transpyloric tubes), have lower morbidity, shorter hospital stays and less cost than those treated with TPN (Figure 17) (Kalfarentzos et al., 1997; McClave et al., 1997; Windsor et al., 1998; Powell et al., 2000; Pupelis et al., 2000; Paraskeva et al., 2001; Duerksen et al., 2002).

Since it is now technically possible to place jejunostomy tubes non-surgically in dogs, through the nose, esophagus or stomach, clinical application of this feeding strategy is not restricted by a surgical procedure. However, it remains open to question whether patients with acute pancreatitis really require jejunal delivery of nutrients. There is evidence that the pancreas of dogs with acute experimental pancreatitis (see CCK induced pancreatitis above), and people with naturally occurring severe pancreatitis, is not as amenable to stimulation as the normal pancreas. Dogs recovering from naturally occurring pancreatitis have also been shown to have subnormal circulating TLI concentrations suggesting that pancreatic enzyme synthesis is downregulated. In addition, it appears that the major benefits of enteral support in acute pancreatitis in people and experimental dogs are due to reductions in the systemic inflammatory response and the translocation of enteric bacteria rather than a reduction in pancreatic stimulation. In this respect probiotic treatment may have a role, and it has been evaluated in people (Olah et al., 2002).

Intestinal permeability and morbidity in dogs with parvovirus are positively impacted by feeding a liquid diet (41% protein, 18% fat, 3% crude fiber) through a nasoesophageal tube supporting the concept that enteral feeding in general, rather than jejunal delivery, is the reason for the beneficial effects of enteral nutrition, though this needs to be critically evaluated (Mohr et al., 2003).

Despite the evidence from human clinical trials and experimental studies in dogs, resistance to enteral feeding of dogs with pancreatitis is anticipated. One common argument used to promote parenteral nutrition in dogs with pancreatitis is that they vomit too frequently to be fed enterally. However, recent studies in dogs with parvovirus should also help to allay this fear as these dogs tolerated naso-esophageal feeding despite severe vomiting and diarrhea, with enterally fed dogs showing faster recovery rates, greater body weight gains and lower intestinal permeability than dogs that were held nil per os (Mohr et al., 2003).

It is not intended that parenteral nutrition be discontinued completely, but that its use be restricted to patients that really need it, for instance those in whom caloric intake is severely and persistently impaired by persistent vomiting. When parenteral nutrition is indicated a choice has to be made between total and partial parenteral nutrition. Partial parenteral nutrition (PPN) is a more practical and manageable procedure than TPN in most settings and has been shown to be a safe and effective way of providing nutrition to dogs with pancreatitis and gastrointestinal disease (Chan et al., 2002). Interestingly dogs that received a combination of enteral and partial parenteral nutrition survived more often than those receiving partial parenteral nutrition exclusively (Chan et al., 2002).

Acute Pancreatitis: Case Study

A - 8 year old female spayed mixed breed dog.

The differential diagnoses are vomiting and abdominal pain (see Table 3). The tacky mucus membranes, fast CRT and heart rate are consistent with hypovolemia secondary to vomiting. The abdominal pain may also be causing the elevated heart rate. The initial diagnostic plan includes a minimum database (PCV, TP, azostick, glucose, urine specific gravity and dipstick), with a CBC, chemistry profile amylase and lipase submitted.

Radiographs (B) show a gas distended duodenum and a slight loss of abdominal detail consistent with peritonitis. An ultrasound is performed that shows an enlarged hypoechoic pancreas (C) and a small amount of free abdominal fluid.

B - Abdominal radiograph
C - Abdominal ultrasound:
1 - Hyperechogenic zone
2 - Fat saponification
3 - Hypoechogenic zone: liquid accumulation

What Diet Should Be Fed to Dogs Recovering from Pancreatitis?

Free choice oral feeding is usually resumed when the appetite returns and vomiting and abdominal pain have subsided. Fat is frequently regarded as the major nutrient to be restricted as it stimulates CCK release and pancreatic secretion. However amino acids are also potent stimulators of pancreatic enzyme secretion and they are not restricted.

High-fat diets (>50 g/1000 kcal) with low protein contents (<20 g/1000 kcal) that have a nutrient profile similar to diet known to induce pancreatitis in dogs must be avoided. Obesity, a risk factor for pancreatitis, should be controlled with a balanced nutritional approach. Elemental diets cause a similar degree of pancreatic stimulation as normal diets.

The composition of a home-made diet must be adapted to the characteristics of the pancreatic disease.
Exocrine pancreatic insufficiency:
Choose highly digestible ingredients. The ideal fat content can vary with individual cases:
- Poor body condition: A diet designed for cachectic animals is suitable (see Chapter 13)
- Fat intolerance: A low fat-diet, suitable for hyperlipidemia is advised (see Chapter 7)
A hypoallergenic diet can be the second choice if the animal doesn't respond or if a dietary allergy is suspected (see Chapter 2).
Acute pancreatitis:
Choose a low fat-diet, suitable for hyperlipidemia (see Chapter 7).