Pancreatitis

2. Exocrine Pancreatic Disease

Introduction

The exocrine pancreas is essential for the optimal digestion and absorption of nutrients (Table 8). Pancreatic acini synthesize and secrete digestive enzymes such as trypsin, lipase and amylase, which break down proteins, lipids and carbohydrates in the proximal duodenum. Bicarbonate rich secretions are released with pancreatic enzymes to maintain an optimal pH for enzyme activity, and secretion of pancreatic intrinsic factor enables the absorption of cobalamin (vitamin B12). In addition, the exocrine pancreas produces bacteriostatic peptides that regulate the upper gastrointestinal flora, and has a role in maintaining the integrity of the intestinal mucosa. The pancreas also has an inbuilt mechanism to prevent it from premature intrapancreatic activation of digestive enzymes and autodigestion.

Pancreatitis is the most common feline exocrine pancreatic disorder, followed by exocrine pancreatic insufficiency; exocrine pancreatic neoplasia and other miscellaneous conditions are less commonly seen in cats.

Pancreatitis

Feline pancreatitis can be difficult to diagnose as clinical signs, laboratory findings and imaging results are often nonspecific (Ferreri et al, 2003). However, pancreatitis has now emerged as a significant disease in cats. It may be acute or chronic and of variable severity. The etiology of most cases of feline pancreatitis is idiopathic. Chronic pancreatitis is the most common form of the disease in cats (De Cock et al, 2007). It is usually mild, and may be only recognized by the development of secondary diabetes mellitus or exocrine pancreatic insufficiency (Steiner & Williams, 2005).

Pancreatitis is sometimes only diagnosed when related conditions, such as hepatic lipidosis, are being investigated. Severe acute pancreatitis (necrotizing, hemorrhagic) can result in extensive pancreatic necrosis and multisystemic complications; however, fulminating pancreatitis associated with severe systemic complications is rare in cats.

Diagnosis

History and Physical Examination

Clinical signs vary depending on the severity of the disease. The most common signs are lethargy, anorexia and dehydration, which are symptoms seen in many feline diseases (Mansfield & Jones, 2001b). Vomiting and cranial abdominal pain are far less common than in dogs with pancreatitis. Cats diagnosed with acute pancreatitis and with concurrent hepatic lipidosis are more likely to be cachectic and have coagulation abnormalities. Some cats with acute pancreatitis are presented because of icterus due to extrahepatic bile duct compression (Zoran, 2006). Severe acute pancreatitis may infrequently result in systemic vasodilatation leading to hypotension and sometimes renal failure. Because cats display less commonly key clinical signs observed in dogs, the diagnosis of pancreatitis is much more difficult and a high index of clinical suspicion is warranted.

Chronic pancreatitis may be subclinical and may cause anorexia and weight loss.

Clinical signs of pancreatitis in cats are nonspecific, including anorexia, lethargy and weight loss. Diagnosis can therefore be difficult, and requires a combination of clinical suspicion, appropriate physical examination findings, elevations in pancreas-specific enzymes and abdominal ultrasonography.

Diagnostic Tests

Hematology, Biochemistries and Urinalysis (Table 9)

Routine laboratory findings are generally nonspecific and cannot distinguish between acute and chronic pancreatitis (Ferreri et al, 2003). Leukocytosis and neutrophilia are more common in acute pancreatitis, and nonregenerative anemia can be found in both acute and chronic disease. Serum biochemical abnormalities are highly variable; most common are elevations in serum liver enzyme activities (alanine amino-transferase [ALT], alkaline phosphatase [ALP]). Severe acute pancreatitis can cause hyperbilirubinemia due to extrahepatic bile duct compression. Azotemia is variably present, and may be pre-renal or renal, either due to dehydration or rarely due to acute renal failure secondary to pancreatitis.

Electrolyte abnormalities (hypokalemia, hypocalcaemia) are frequently seen in severe cases. Hypocalcemia (total and serum ionized) appears to be a more frequent finding in cats than in dogs; it may result from several mechanisms, including peripancreatic formation of calcium salts with fatty acids (fat saponification), and is associated with a worse prognosis (Kimmel et al, 2001). Other abnormalities may include hypoalbuminemia, hypercholesterolemia and hyperglycemia.

Urinalysis often reveals an elevated urine specific gravity secondary to dehydration. In severe cases acute renal failure may ensue, resulting in reduced urine specific gravity and casts in the sediment.

None of these findings are specific, but the tests are nonetheless important because they serve to rule out disorders other than pancreatitis and to assess the overall status of the patient.

Pancreas Specific Enzymes

Measurement of serum lipase and amylase activities is very insensitive and of no clinical value in the diagnosis of feline pancreatitis. Determination of serum feline trypsin-like immunoreactivity (fTLI), which is specific for exocrine pancreatic function, is more helpful but its sensitivity for detection of pancreatitis in cats is less than 50%, making it a suboptimal diagnostic test (Swift et al, 2000; Steiner, 2003;Forman et al, 2004).

Recently, a serum feline pancreatic lipase immunoreactivity (fPLI) test has been validated, which appears to be a more sensitive and specific test for the diagnosis of feline pancreatitis, more so for acute than chronic pancreatitis (Forman et al, 2004; Steiner, 2004).

Diagnostic Imaging

Radiography – The sensitivity of abdominal radiography is generally low for the diagnosis of feline pancreatitis, and especially for chronic pancreatitis. Radiographic abnormalities in acute pancreatitis may include a generalized or focal loss of serosal detail (suggesting peritonitis or peritoneal effusion), increased opacity or the presence of a mass in the area of the pancreas, displacement of the duodenum and/or a dilated and hypomotile duodenum. Cats with concurrent hepatic lipidosis often have hepatomegaly. These changes occur much less commonly than in canine acute pancreatitis, and are not specific (Whittemore & Campbell, 2005).

Ultrasonography – Abdominal ultrasonography is more specific and sensitive for detecting pancreatic abnormalities, and is currently one of the most commonly used tools for the diagnosis of pancreatitis in cats. It also allows the evaluation of concurrent disease, e.g., liver disease or biliary obstruction. Ultrasound is widely available today, although sonographic examination of the pancreas requires a high level of operator expertise. Changes identified include pancreatic swelling, changes in echogenicity of the pancreas (hypoechogenicity in acute pancreatitis and hyperechogenicity in chronic pancreatitis and fibrosis) (Figure 21 & Figure 22), hyperechoic peripancreatic fat and mesentery, abdominal effusion, a dilated common bile duct, and less frequently a mass effect in the area of the pancreas (Figure 23). Cavities of the pancreas are generally due to abscesses or pseudocyst formation, and appear as anechoic or hypoechoic cavities, possibly with a thickened wall (Figure 24). Mild pancreatitis may however be more difficult to diagnose via abdominal ultrasound.

Figure 21. Ultrasound image of a cat with acute pancreatitis. The cat had a serum fTLI concentration >400 mg/L. Ultrasound shows a diffusely hypoechoic parenchyma. The pancreas is not enlarged. (© Courtesy of CR Lamb, Royal Veterinary College).

Figure 22. Chronic active pancreatic necrosis in a diabetic cat. Ultrasound shows a diffusely hypoechoic, enlarged pancreas. (© Courtesy of CR Lamb, Royal Veterinary College).

Figure 23. Pancreatic pseudocyst in a cat. The lateral abdominal radiograph indicates an oblong soft tissue opacity along the ventral abdomen. (© Courtesy of CR Lamb, Royal Veterinary College).

Figure 24. Ultrasound scan of a cat with a pancreatic pseudocyst. The ultrasound scan shows a cavitary mass with thick irregular walls. (© Courtesy of CR Lamb, Royal Veterinary College).

Computed Tomography (CT) – Other imaging modalities, such as CT-scanning, are more expensive and thought to be less helpful than abdominal ultrasonography (Gerhardt et al, 2001; Forman et al, 2004).

Biopsy

Ultrasound guided fine needle aspiration is relatively safe and helps in identification of the underlying pancreatic disease, e.g., in differentiating between pancreatitis and neoplasia. However, the patchy distribution of pancreatic inflammation can limit its usefulness, and multiple aspirates will be needed. Laparoscopy and laparotomy allow visualization of the pancreas and biopsy of parts that look abnormal, as well as inspection of other abdominal organs (e.g., liver, biliary tract, intestine). The latter is important in the cat because of the high incidence of concurrent disease in this species. Surgical biopsy procedures are however expensive and invasive, while cats with acute pancreatitis may be poor anesthetic risks.

Differential Diagnosis

The clinical signs of feline pancreatitis are nonspecific, but this disease should however be suspected in any cat with evidence of hepatic, biliary or inflammatory bowel disease.

Most cases of pancreatitis are seen in domestic short-hair cats. There is no breed or sex predisposition. (© Yves Lanceau/Royal Canin).

Pancreatic neoplasia is much less common than pancreatitis, but signs and ultrasonographic findings can be similar in cats (Seaman, 2004; Hecht et al, 2007). Identification of a pancreatic mass and lymphadenopathy upon ultrasonography may be helpful, but fine-needle aspiration or surgical biopsy is needed for definitive diagnosis.

Epidemiology

Etiology

Most feline pancreatitis cases are idiopathic, and causes and risk factors have been described in only a small number of cases. Traumatic pancreatitis associated with road traffic accidents or falls from a great height ("high rise syndrome") has been reported in some cases. Several infectious agents have been implicated, although a cause-and-effect relationship has only been established for Toxoplasma gondii and in very rare cases aberrant migration of the feline liver fluke (Amphimerus pseudofelineus). Feline herpesvirus, coronavirus (feline infectious peritonitis -FIP-) and panleukopenia virus are putative causative factors for pancreatitis in cats, but there is little or no scientific evidence to support this (Steiner & Williams, 1999; Mansfield & Jones, 2001a). Drugs have been implicated as causing pancreatitis in humans and dogs, but this is poorly documented in cats. Pancreatitis was reported in two cats following topical administration of the organophosphate fenthion (Hill & Van Winkle, 1993).

Risk Factors

There are few known risk factors for the development of pancreatitis in cats. Many cats with chronic pancreatitis have concurrent biliary tract and/or gastrointestinal tract disease ("triad disease"), but the cause-and-effect relationship remains unclear. The incidence of chronic pancreatitis is however significantly correlated with increasing age (De Cock et al, 2007). In contrast to dogs, there is no evidence that overweight body condition, nutritional factors (ingestion of highfat meals) or endocrine diseases (hyperadrenocorticism) play a role in the etiology of feline pancreatitis. Pancreatitis may occur in cats of any breeds. An older report suggesting that Siamese cats were at increased risk has not been confirmed in recent studies. There is no sex predisposition.

Pathophysiological Mechanisms

Regardless of the initiating cause, pancreatitis is thought to be due to premature intrapancreatic activation of trypsinogen which, when activated to trypsin, activates other digestive proenzymes resulting in a local and systemic inflammatory response. Under normal conditions this does not happen due to a number of protective mechanisms, which include:

1. Synthesis, storage and secretion of pancreatic enzymes as zymogens (inactive proenzymes) that must be activated by trypsin within the gut prior to being functional
2. Strict segregation between lysosomes and zymogens
3. Secretion of pancreatic secretory trypsin inhibitor.

Pancreatitis develops when all these protective mechanisms are overwhelmed, resulting in fusion between lysosomes and zymogens, and intrapancreatic activation of digestive enzymes (Steiner & Williams, 1999).

Acute mild pancreatitis can be self-limiting, and usually has few symptoms. Severe acute pancreatitis is uncommon in cats, but can have serious local and systemic complications. Activated digestive enzymes cause local effects, such as inflammation, hemorrhage, acinar cell necrosis, and peripancreatic fat necrosis (Figure 25). Cytokines released into the blood stream may cause systemic effects, including systemic inflammatory changes, vasodilatation leading to hypotension, pulmonary edema, disseminated intravascular coagulation (DIC), central neurological deficits, and multi-organ failure. Depletion of pancreatic acinar glutathione can furthermore stimulate oxidative stress that contributes to tissue injury. However, the exact pathophysiology of spontaneous pancreatitis in cats remains speculative.

The goals of management are removal of the inciting cause if possible, provision of supportive and symptomatic therapy, and monitoring for and treatment of complications. Nutritional support is especially important in cats since anorexia predisposes them to hepatic lipidosis.

Figure 25. Peripancreatic fat necrosis. Exploratory laparotomy and histopathology confirm severe multifocal fat necrosis in a cat with fatal acute pancreatitis. (© Courtesy of KW Simpson).

Treatment

Medical Management

Acute Pancreatitis

Treatment for feline acute pancreatitis is mainly supportive and aimed at restoring and maintaining fluid and electrolyte balance, inhibiting inflammatory mediators and pancreatic enzymes, controlling pain and vomiting, and management of complications and/or concurrent diseases (Simpson, 2005). Initial fluid therapy is usually with Lactated Ringers solution; potassium and glucose should be added where necessary based upon the results of serum biochemistries. The type of fluid should then be adjusted based upon measurements of electrolyte levels and pH. Efforts should also be made to identify and remove an underlying cause; however, more than 90% of cases are idiopathic.

In severe acute pancreatitis, other therapeutic strategies may furthermore involve plasma administration (20 mL/kg IV) to replenish α2-macroglobulin, a scavenger protein for activated proteases in serum. However, although it has been reported to be of value in dogs with pancreatitis, little is known about its usefulness in cats.

Abdominal pain is commonly recognized in humans and dogs but not in cats with pancreatitis, likely because many cats do not show clear signs of abdominal discomfort. They may however benefit significantly from analgesic therapy, and the presence of abdominal pain should be suspected. Treatment with analgesic drugs e.g., (buprenorphine 0.005 - 0.1 mg/kg SC q 6 - 12 hrs) can help cats with acute pancreatitis to feel better and promote eating (Whittemore & Campbell, 2005).

It is common practice to give parenteral antibiotics during this supportive period, but cats with pancreatitis seldom have infectious complications. Antibiotic administration is best avoided unless the cat is febrile and/or has toxic changes on the white blood cell count.

Concurrent diseases are common in feline pancreatitis, and need to be addressed to improve response to therapy (Simpson, 2005). Associated diseases include inflammatory bowel disease, cholangiohepatitis and interstitial nephritis (Weiss et al, 1996). Concurrent hepatic lipidosis is common (Akol et al, 2001), which emphasizes the need for early nutritional support.

Chronic Pancreatitis

Medical management is supportive and mostly focuses on treatment of secondary diabetes mellitus and/or exocrine pancreatic insufficiency. Whenever possible the underlying cause should be removed. Exposure to unnecessary drugs should be avoided, and consideration should be given to the treatment of pancreatic flukes, especially in areas where they are known to be prevalent. Concurrent diseases, notably inflammatory bowel disease, cholangiohepatitis and interstitial nephritis, are common in cats with chronic pancreatitis, but little is known about how to best treat these in conjunction with managing the pancreatitis (Ferreri et al, 2003).

Abdominal pain is frequent in people with chronic pancreatitis and is likely to occur in cats as well, although it is generally poorly recognized. Meperidine or butorphanol can be used parenterally. This has not been documented in cats, but trial therapy with pancreatic enzymes should be considered in patients with chronic pancreatitis that show either abdominal pain or anorexia attributable to abdominal discomfort (Steiner & Williams, 2005). Supplementation with pancreatic enzymes may be helpful to reduce abdominal pain by a negative feedback on endogenous pancreatic enzyme secretion.

Nutritional support is essential in cats with acute pancreatitis, since they are generally anorexic and often have concurrent hepatic lipidosis. Nutrition furthermore helps tissue repair and recovery, and can modulate the inflammatory response.

Nutritional Management (Table 10)

To Feed or Not to Feed

The traditional recommendation for patients with acute pancreatitis is not to feed orally for three to four days in order to prevent further pancreatic stimulation ("rest the pancreas"). This recommendation is justified in patients that vomit, but most cats with acute pancreatitis do not vomit. The issue is complicated further in cats by the fact that cats with severe pancreatitis are anorexic and often develop hepatic lipidosis, which worsens their prognosis (Akol et al, 2001). Pancreatitis is a catabolic state in which metabolic and energy demands can be very high. Starvation will only serve to compound malnutrition and will also adversely affect immune response and bowel mucosal integrity. Cats with pancreatitis should therefore receive nutritional support at an early stage. There is no clinical impression that such enteral nutrition exacerbates the course of pancreatitis, and in fact cats clearly do better overall when nutritional support is given.

If the cat is not eating on its own within three days, nutritional support via a feeding tube is indicated to prevent or treat hepatic lipidosis, protein/calorie malnutrition and immunosuppression.

How to Feed

Oral force feeding is not recommended since it is difficult to achieve the appropriate levels of caloric intake by this method, and also because it can induce food aversion. The choice is then between enteral or parenteral nutrition. There is increasing evidence in humans and animals that enteral nutrition is superior to parenteral nutrition in the treatment of acute pancreatitis (Marik & Zaloga, 2005; Simpson, 2005; Makola et al, 2007). Enteral nutrition prevents intestinal mucosal atrophy and bacterial translocation which accompany parenteral nutrition. It is also more economical, has less risk of septic complications and is far less complicated to use. The simplest and most widely used methods of enteral feeding are via a nasoesphageal, esophagostomy or percutaneous endoscopic gastrostomy (PEG) tube (seechapter 12). Postpyloric feeding via a jejunostomy tube (distal to the site of pancreatic stimulation) has the theoretical advantage of minimizing pancreatic stimulation, but there are now several studies in human patients that the nasogastric route may be just as effective and safer. Jejunostomy tube placement historically required invasive surgery, but recently a percutaneous endoscopic transpyloric placement technique has been described (Jergens et al, 2007). It remains however open whether cats with acute pancreatitis really require jejunal feeding.

Parenteral nutrition may be necessary for cats in which persistent vomiting cannot be controlled by anti-emetic treatment; it is however expensive, difficult to administer in practice, and may cause complications such as sepsis.

What Diet to Feed

The diet for patients with pancreatitis should be highly digestible. Dietary fat restriction is recommended for human and canine patients with pancreatitis in order to reduce pancreatic stimulation, but is less applicable to felines. Cats are obligate carnivores and require fairly high dietary fat levels, and in contrast to dogs there is little clinical evidence to suggest that dietary fat restriction influences the outcome of feline pancreatitis. In addition, low-fat diets are energy restricted and not a good choice for sick cats with poor appetites. The best compromise is to select a palatable, complete and balanced diet formulated for maintenance with a moderate fat content (10 - 12% on a dry matter basis). The important thing is to stay away from a high fat diet (>16 % fat on a dry matter basis), especially in those cats that have both pancreatitis and diabetes mellitus (Steiner J, personal communication 2007).

Dietary protein should be of good quality and meet the cat’s requirements for maintenance and tissue repair. However, diets excessively high in protein should be avoided in order to minimize pancreatic stimulation by peptides. Novel antigen diets may be useful in cats with pancreatitis and concurrent inflammatory bowel disease (Biourge & Fontaine, 2004).

Dietary Supplements

Antioxidants – Oxidative stress caused by inflammatory mediators can aggravate severe acute pancreatitis in humans (Schulz et al, 2003), although the role of antioxidant treatment in its management is controversial (Johnson, 2007). There are no data about the role of antioxidants in the management of feline pancreatitis.

Fatty Acids – Supplementation with n-3 polyunsaturated fatty acids (fish oil) can ameliorate inflammation through modulation of eicosanoid synthesis. A clinical trial in human patients with acute pancreatitis suggested a clinical benefit based upon shortened time of hospital stay and jejunal feeding (Lasztity et al, 2005). Its use in cats with exocrine pancreatic disease has not yet been evaluated.

Cobalamin – Cobalamin malabsorption is common, because intrinsic factor (IF), a cobalamin binding protein that promotes cobalamin absorption in the ileum, is produced only by the pancreas in cats (as opposed to the stomach and pancreas in dogs). Cobalamin deficiency is even greater in cats with concurrent small intestinal disease. Cats with subnormal serum cobalamin concentrations should be supplemented parenterally (SQ or IM, 250 μg once a week for six weeks and then monthly) (Simpson et al, 2001). The necessity for further treatments should be assessed by regular measurement of serum cobalamin concentrations.

Vitamin K – Coagulation abnormalities should be treated with parenteral vitamin K; in cats with severe necrotizing pancreatitis, the possibility of disseminated intravascular coagulation should be assessed, which may require administration of fresh frozen plasma (10 - 20 mL/kg).