Inflammatory disease of the human pancreas is usually divided into acute and chronic types based on a combination of clinical and pathological criteria, this classification may be loosely applied to cats and dogs ().
• Acute pancreatitis refers to inflammation of the pancreas with a sudden onset and little or no permanent pathological change after recovery.
• Chronic pancreatitis is a continuing inflammatory disease characterized by irreversible morphological change (fibrosis and atrophy) and it possibly leads to permanent impairment of function.
Both acute and chronic pancreatitis may be further subdivided based on the aetiology, if known, and the severity.
Complications of both types of pancreatitis may include:
• Fluid accumulations around the inflamed pancreas
• Pseudocyst (a collection of sterile pancreatic juice enclosed by fibrous or granulation tissue)
• Localized necrosis
• Pancreatic abscess (a circumscribed collection of pus, usually in proximity to the pancreas, containing little or no pancreatic necrosis).
• Infected necrosis (from which bacteria can be cultured — very rare).
Classification based on aetiology is desirable, but this is rarely possible.
When examined at exploratory laparotomy or necropsy, the affected pancreas is often oedematous, swollen and soft, and there may be fibrinous adhesions to adjacent organs. Acute fluid collections (often bloodstained and containing fat droplets, but lacking a wall of granulation or fibrous tissue) may be seen in or near the pancreas or throughout the peritoneal cavity, particularly in cats. Severely affected areas of pancreas may be liquefied and pseudocysts may have formed. Haemorrhages may be present in the omentum and in the pancreas, and there are often chalky areas of fat necrosis both adjacent to the pancreas and also in fat as far away as the cranial mediastinum (). Histologically there is extensive multifocal infiltration by neutrophils and varying degrees of haemorrhage, necrosis, oedema and vessel thrombosis.
If an initial acute episode is not fatal, there may be complete resolution or alternatively the inflammatory process may smoulder continuously but asymplomatically. Extensive destruction of pancreatic tissue may Reduce the gland to a few distorted lobules adjacent to where the ducts enter the duodenum () before clinical signs are again evident.
Recent reports have described acute necrotizing pancreatitis in cats similar to that seen in dogs, as well as a histologically distinct suppurative form. However, chronic mild interstitial pancreatitis characterized by inflammation of interstitial tissue, apparently associated with the ducts, is the type of pancreatic inflammation most commonly reported in cats. This latter type of pancreatitis is often accompanied by cholangiohepatitis, inflammatory bowel disease or nephritis, any of which may be of greater clinical significance than the pancreatitis.
It is generally believed that pancreatitis develops when there is activation of digestive enzymes within the gland with resultant pancreatic autodigestion. In many experimental models of pancreatitis, abnormal fusion of lysosomes and zymogen granules occurs due to failure of normal secretary processes (). Lysosomal proteases then activate trypsinogen since PSTI is ineffective at the acid pH present in lysosomes. Subsequent increased capillary permeability, due to endothelial cell membrane damage, leads to pancreatic oedema. Similar changes in duct cell permeability may also trigger other pathophysiological mechanisms and thereby exacerbate pancreatitis.
Once intracellular and intraductal activation of trypsinogens to trypsins takes place, further activation of progressively larger amounts of proteases and phospholipase occurs. This is associated with transformation of mild oedematous pancreatic inflammation to haemorrhagic or necrotic pancreatitis with multisystem involvement and consumption of plasma protease inhibitors (). Once enzyme activation is initiated, numerous inflammatory mediators and free radicals are also important in the progression of pancreatitis. These mediators are mostly released from neutrophils and macrophages and include tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1 ), IL-2, IL-6, IL-8, IL-10, interferon-α (INF-α), INF-γ, nitric oxide (NO) and platelet activating factor (PAF).
Plasma α-macroglobulins and α1-proteinase inhibitor () are vital in protecting against the otherwise fatal effects of proteolytic enzymes in the vascular space. α-Macroglobulins are particularly important in this regard. Dogs tolerate experimental intravenous injections of trypsin or chymotrypsin without showing adverse effects provided that free α-macroglobulins are available to bind the active proteases. Once α-macroglobulins are utilized, even though there is free α-proteinase inhibitor, dogs die rapidly from acute disseminated intravascular coagulation and shock as the free proteases activate the kinin, coagulation, fibrinolytic and complement cascade systems ().
Binding of proteases by α-macroglobulins result in a change in conformation which allows the complex to be recognized and rapidly cleared from the plasma by the monocyte — macrophage system. This removal is important since α-macroglobulin-bound proteases retain catalytic activity, particularly against low molecular weight substrates () and normal functioning of the monocyte — macrophage system is an important factor determining survival in experimental pancreatitis.
The inciting cause of pancreatitis in the dog is usually unknown but the following potential causes and risk factors should be considered:
- Nutrition, hypertriglyceridaemia and hereditary factors
- Drugs, toxins and hypercalcaemia
- Duct obstruction
- Duodenal and biliary reflux, pancreatic trauma and pancreatic ischaemia and reperfusion.
Nutrition, hypertriglycerridamia andhereditary factors: It has been suggested that pancreatitis is more prevalent in obese animals and it has been shown that the disease is less severe when induced in lean dogs. Low protein, high fat diets may induce pancreatitis; pancreatitis is more severe when induced in dogs fed a high fat diet and less severe when induced in lean dogs fed the same diet. Malnutrition has also been reported to cause pancreatic inflammation and atrophy in human patients and pancreatitis has been observed after refeeding following a prolonged fast. Feeding the amino acid analogue ethionine induces pancreatitis in several species, including dogs and cats.
Hypertriglyceridaemia, often grossly apparent, is common in dogs with acute pancreatitis and may develop as a result of abdominal fat necrosis, or may be a cause of the disease in some cases. Some familial hypertriglyceridaemias in humans are associated with frequent episodes of pancreatitis that respond to control of serum triglyceride concentrations. It is widely believed that the high prevalence of pancreatitis observed in Miniature Schnauzers may be related to idiopathic hypertriglyceridaemia. There is also anecdotal evidence that pancreatitis in dogs often develops following a fatty meal.
Hereditary pancreatitis is well documented in human beings. Several contributory mutations of the cationic trypsinogen gene, as well as some other genes (PSTI) have been identified. Similar mutations may be present in dogs and cats, but have not yet been identified.
Drugs, toxins and hypercalcaemia: More than 50 drugs and drug classes have been implicated as a cause of pancreatitis in human beings, although absolute proof of a causal relationship is often lacking. Suspect drugs that are also commonly used in veterinary medicine include L-asparaginase, azathioprine, oestrogen, furosemide, potassium bromide, salicylates, sulphonamides, tetracyclines, thiazide diuretics and vinca alkaloids. Corticosteroids have recently been removed from the list of drugs that may induce pancreatitis in human beings. There is also little credible evidence that glucocorticoid administration causes pancreatitis in dogs, with the possible exception of the use of high doses in association with spinal trauma. Nonetheless, it is probably wise to discontinue the use of any drug in patients with pancreatitis of undetermined cause unless a specific indication for continued use exists and no alternatives are available.
Administration of cholinesterase inhibitor insecticides and cholinergic agonists has been associated with the development of pancreatitis, probably by causing hyperstimulation. Scorpion stings in human beings can cause pancreatitis and experimental administration of scorpion venom to dogs also elicits pancreatitis. Zinc toxicosis has also been reported to cause pancreatitis in the dog. Also, both spontaneous and iatrogenie hypercalcaemia may cause pancreatitis in dogs.
Duct obstruction: Experimental obstruction of the pancreatic ducts produces atrophy and fibrosis, although inflammation and oedema may also develop when pancreatic secretion is stimulated. Clinical conditions that may lead to partial or complete obstruction of the pancreatic ducts include biliary calculi, sphincter spasm, oedema of the duct or duodenal wall, neoplastic conditions, parasites, trauma and surgical interference. Biliary calculi are a major cause of pancreatitis in humans but this has not been reported in dogs, presumably because of the low prevalence of biliary stones in this species and because dogs have an accessory pancreatic duct that does not communicate with the common bile duct and serves as the main pancreatic duct. Congenital anomalies of the pancreatic duct system may predispose to pancreatitis in humans and similar mechanisms may occur in the dog and cat but have not been documented.
Duodenal and biliary reflux, pancreatic trauma and pancreatic ischaemia and reperfusion: Reflux of duodenal juice into the pancreatic ducts secondary to surgical creation of a closed duodenal loop causes severe acute pancreatitis. Under normal circumstances such reflux is unlikely to occur since the duct opening is surrounded by a specialized compact smooth mucosa over the duodenal papilla and is equipped with an independent sphincter muscle. However, this antireflux mechanism may sometimes fail owing to an abnormally high duodenal pressure, such as may occur during vomiting or after blunt trauma to the abdominal cavity.
Surgical manipulation as well as blunt abdominal trauma are potential causes of pancreatitis but reports of pancreatitis following such insults are rare. Pancreatitis following pancreatic biopsy is extremely rare and is also uncommon following resection of pancreatic neoplasms.
Experimental and clinical reports have indicated that ischaemia is important in the pathogenesis of acute pancreatitis, either as a primary cause or as an exacerbating influence. Pancreatic ischaemia may develop during shock or severe acute anaemia, or during temporary occlusion of venous outflow, either during surgical manipulation in the cranial abdomen or secondary to hypotension during general anaesthesia. This latter mechanism may explain some instances of postoperative pancreatitis when organs remote from the pancreas have undergone surgery.
Miscellaneous: Viral, mycoplasmal and parasitic infections may be associated with pancreatitis, although this is usually recognized as part of a more generalized disease process. Recently, pancreatitis has been recognized as a potential complication of babesiosis, perhaps as a consequence of anaemia and ischaemia. It is unknown whether bacterial infection plays a role in the development of pancreatitis in some cases but concomitant bacterial infection does increase the severity of experimental pancreatitis. Pancreatitis may occur in association with end stage renal failure; although this is rare. It is likely that renal failure secondary to acute pancreatitis is encountered more frequently. Acute pancreatitis has been observed in patients with liver disease, perhaps reflecting vascular compromise secondary to coagulation abnormalities, accumulation of toxins (endotoxins, bile acids) secondary to impaired liver function, response to a common initial cause, or reaction to drugs given in an attempt to manage the hepatic failure. Finally, autoimmune mechanisms that respond to glucocorticoid therapy have been incriminated in a small subset of human patients with pancreatic inflammation, and similar mechanisms may play a role in some veterinary patients, particularly in cats.
History and clinical signs: Dogs with acute pancreatitis are usually presented because of depression, anorexia and vomiting. Severe acute disease may be associated with shock and collapse, while other cases may have a history of less dramatic signs extending over several weeks. Signs of pain may be elicited by abdominal palpation. A cranial abdominal mass is palpable in some cases and occasionally there is mild ascites. Most affected animals are mildly to moderately dehydrated and febrile. Uncommon systemic complications of pancreatitis that may be apparent on physical examination include jaundice, respiratory distress, bleeding disorders and cardiac arrhythmias. While patients of any age may develop pancreatitis, affected animals are usually middle-aged or older, and sometimes obese, and the onset of signs may have followed ingestion of a large amount of fatty food. The clinical signs of mild acute pancreatitis and chronic pancreatitis in dogs are poorly documented but are probably extremely variable and non-specific. The disease may not be clinically apparent at all. As a consequence mild disease probably remains undiagnosed in most cases. The history of cats with pancreatitis is extremely variable. Most cats with severe disease present with a history of lethargy and anorexia. Key clinical signs of acute pancreatitis in dogs and human beings, vomiting and abdominal pain, have been reported in only 35% and 25% respectively, of cats with severe pancreatitis. Hypothermia, dyspnoea, diarrhoea and ataxia have also been reported. Mild chronic pancreatitis may be subclinical or may cause anorexia and weight loss.
Diagnostic imaging: Definitive radiographic evidence of pancreatitis is rarely seen, the most common finding being a somewhat subjective loss of visceral detail (‘ground glass appearance’) in the cranial abdomen (). Classical abnormalities reported with pancreatitis include:
• Increased density and diminished contrast and granularity in the right cranial abdomen
• Displacement of the stomach to the left
• Widening of the angle between the pyloric antrum and the proximal duodenum ”
• Displacement of the descending duodenum to the right
• Presence of a mass medial to the descending duodenum
• Static gas pattern in, or thickened walls of, the descending duodenum
• Static gas pattern in, or caudal displacement of, the transverse colon
• Gastric distention suggestive of gastric outlet obstruction
• Delayed passage of barium through the stomach and duodenum with corrugation of the duodenal wall indicating abnormal peristalsis.
Unfortunately these findings are subjective and definitive radiographic evidence of pancreatitis is usually not present. However, abdominal radiography may provide evidence to rule in or rule out alternative diagnoses.
Abdominal ultrasonography is highly specific for pancreatitis when stringent criteria are applied, with a sensitivity of up to approximately 70% in dogs and 300 in cats. Enlargement of the pancreas and/or localized peritoneal effusion are not sufficient for a diagnosis. Changes in echogenicity are quite usetul ().
Decreased echogenicity indicates pancreatic necrosis, which is often associated with hyperechogenicity the peripancreatic region. Hyperechogenicity of the pancreatic parenchyma itself indicates pancreatic fibrosis and can be seen in cases of chronic pancreatitis. Pancreatic duct dilatation has been reported in cats. Serial examinations are particularly useful for identification and management of pancreatic complications, such as pancreatic pseudocyst or abscess associated with cystic masses.
Routine laboratory tests: Leucocytosis is a common haematological finding inacute pancreatitis. The packed cell volume may be increased as a result of dehydration, although in many cases particularly in cats anaemia is observed following rehydration.
Azotaemia is frequently present and usually reflects dehydration. Sometimes there may be acute renal failure secondary to hypovolaemia or to other mechanisms, such ascirculating vasotoxic agents and plugging of the renal microvasculature by either fat deposits or microthrombi from the sites of disseminated intravascular coagulation.
Liver enzyme activities are often increased, reflecting hepatocellular injury as a result of either hepatic ischaemia or exposure of the liver to high concentrations of toxic products delivered from the pancreas in portal blood. In some cases, particularly in cats, there is hyperbilirubinaemia and sometimes clinically apparent jaundice, which may indicate severe hepatocelluiar damage and/or intra-hepatic and extra-hepatic obstruction to bile flow.
Hyperglycaemia is common in dogs and cats with necrotizing pancreatitis, probably as a result of hyperglucagonaemia and stress-related increases in the concentrations of catechol amines and cortisol. Some patients develop diabetes mellitus and require insulin replacement therapy. In contrast, cats with suppurative pancreatitis often develop hypoglycaemia.
Hypercholesterolaemia and hypertriglyceridaemia are very common in dogs, and hyperlipaemia is often grossly apparent even though food has not been ingested for many hours. Extreme hyperlipaemia may prevent accurate determination of other serum biochemical values. Analysis of plasma lipids has not revealed any clear-cut pattern characteristic of acute pancreatitis. Hypocalcaemia has often been reported but is usually mild to moderate and associated with hypoalbuminaemia. Low ionized calcium in cats has been reported to be a poor prognostic finding.
Serum concentrations of pancreatic digestive enzymes (amylase, lipase, phospholipase A2, trypsin-like immunoreactivity (TLI) and pancreatic lipase immunoreactivity (PLI)) are often increased in animals with pancreatitis. Conventional catalytic assays and newer, highly specific, immunoassays exist () and it is important that a method appropriate for each species be utilized. Immunoassays are generally only applicable to the species for which they were developed. At the time of writing, feline TLI (fTLI), feline PLI (fPLI) and canine PLI (cPLI) assays are only performed at the author’s laboratory.
Pancreatitis: Acute treatment
The treatment of acute pancreatitis involves correction and maintenance of fluid and electrolyte balances while the underlying cause, if known, is rectified. The patient is then supported whilst allowing the pancreas to recover from the inflammatory episode. Recent reports have challenged the traditional logic and wisdom of withholding food to ‘rest’ the pancreas, however, and both parenteral and enteral nutrition have been well tolerated by patients with pancreatitis. There is also evidence that enteral nutrition may be superior to parenteral nutrition. Oral intake should probably only be restricted in those patients with incessant vomiting and then for as short a period as possible.
Mild cases of pancreatitis are probably self-limiting and may spontaneously improve after 1 or 2 days of basic supportive therapy. Other patients require aggressive fluid therapy over several days to treat severe dehydration and ongoing fluid electrolyte loss due to vomiting and diarrhoea. Most animals become hypokalaemic during such therapy and serum potassium should be monitored and supplemented parenterally if required. Serum creatinine or urea levels should also be measured to monitor renal function. While metabolic acidosis is probably common in acute pancreatitis, this may not always be the case and vomiting patients may be alkalotic. Care should be taken that bicarbonate administration to rectify acidosis does not precipitate signs of hypocalcaemia in individuals with borderline low calcium levels.
Antibiotic therapy: In contrast to human beings, cats and dogs with pancreatitis rarely have infectious complications and antibiotic therapy would appear to be of minimal benefit. However, for cases where there is good evidence for pancreatic infection it should be noted that trimethoprim-sulphonamide and enrofloxacin penetrate well into the exocrine pancreas in dogs.
Analgesic therapy: Analgesic therapy (e.g. subcutaneous pethidine hydrochloride, transdermal fentanyl, morphine by constant rate intravenous infusion or, for dogs, intraperitoneal lidocaine or bupivacaine) should be given to provide relief of pain, even if signs of pain are not apparent.
Transfusion: The transfusion of plasma or whole blood to replace α-macroglobulins may be life-saving in patients with severe disease and has the additional benefit of maintaining plasma albumin concentrations. Albumin is probably beneficial in pancreatitis because of its oncotic properties that not only help maintain blood volume and prevent pancreatic ischaemia, but also limit pancreatic oedema formation. Low molecular weight dextrans have also been used to expand plasma volume but they may aggravate bleeding tendencies, contain no protease inhibitor and provide no major advantages over plasma administration. A hypertonic saline-dextran 70 combination was shown to be effective in maintaining cardiac function without massive fluid administration, thereby avoiding pulmonary hypertension and oedema that can accompany therapy wi.th lactated Ringer’s solution alone. Hyperoncotic ultra-high molecular weight dextran solutions have recently been shown to reduce trypsinogen activation, prevent acinar necrosis and lower mortality in rodent pancreatitis, perhaps by promoting pancreatic microcirculation.
Corticosteroids: These should be given only on a short-term basis to animals in shock associated with fulminating pancreatitis, and then in concert with fluids and plasma, as described above. Longer periods of administration may impair removal of α-macroglobulin-bound proteases from the plasma by the monocyte — macrophage system, with resultant complications due to systemic effects of circulating uninhibited enzymes.
Somatostatin and dopamine: Somatostatin and its analogues may reduce complications and improve survival in human patients but there is not yet sufficient evidence to recommend their routine use. Infusion of dopamine at a dose that stimulates both dopaminergic and β-adrenergic receptors (i.e. 5 μg/kg/min i.v.) is helpful in reducing severity and progression of some feline models of pancreatitis; it is thought that the beneficial effect of dopamine is related to reduction of microvascular permeability rather than to promotion of pancreatic blood flow.
Secretion prevention: Nasogastric suctioning of gastric secretions and use of antacids or cimetidine have been recommended in order to indirectly inhibit pancreatic secretion. However, none of these methods has been consistently shown to be effective and their value has largely been discounted. Attempts to rest the pancreas using direct inhibitors of secretion such as atropine, acetazolamide, glucagon and calcitonin have not proved to be effective. Secretin, the hormone that naturally stimulates pancreatic secretion, was beneficial in a rat model of pancreatitis when given at a high dose intravenously.
Enzyme inhibitors: Administration of a variety of naturally occurring and synthetic enzyme inhibitors with selective actions against individual pancreatic digestive enzymes, as well as free-radical scavengers such as selenium, have shown promise in experimental studies but their value remains to be conclusively demonstrated in clinical trials.
Peritoneal dialysis: The use of peritoneal dialysis to remove toxic material accumulated in the peritoneal cavity is beneficial experimentally and is thought by many to be useful in human patients. While impractical in some veterinary practices, peritoneal dialysis may be of value in some cases. Certainly, in those patients where acute pancreatitis is confirmed at exploratory laparotomy removal of as much free fluid as possible followed by abdominal lavage is advisable. Reports of surgical intervention to debride and drain affected areas are not favourable, although in one report of six dogs with fibrotic obstructive masses, cholecystoduodenostomy was followed by recovery. Many patients that develop obstructive jaundice in association with acute pancreatitis recover spontaneously over 2 — 3 weeks with conventional supportive care alone.
Diet: Small amounts of water should be offered after the patient has stopped vomiting. If there is no recurrence of clinical signs, food may be gradually reintroduced. The diet should have a high carbohydrate content (rice, pasta, potatoes) since protein and fat are more potent stimulants of pancreatic secretion and are therefore more likely to promote a relapse. If there is continued improvement, gradual introduction of a low fat content maintenance diet should be attempted. Another period of food deprivation should be instituted if signs of pancreatitis recur. While the prognosis is poor for those patients that repeatedly cannot tolerate food, total parenteral nutrition may be beneficial by sustaining such patients while the digestive system is rested for 7-10 days.
Supportive care: Hyperglycaemia is often mild and transient but in some cases diabetes mellitus may develop, requiring treatment with insulin. Respiratory distress, ineurological problems, cardiovascular abnormalities, bleeding disorders and acute renal failure are all poor prognostic indicators. Attempts should be made to manage these complications by appropriate supportive measures ().
Treatment of complications
Use of ultrasound imaging has contributed to increased recognition of pancreatic masses in patients with pancreatitis.
Pancreatic pseudocysts have been described in dogs and cats. Clinical signs are those associated with pancreatitis. On abdominal ultrasound a cystic structure in close proximity to the pancreas can be identified. Aspiration of the pseudocyst is relatively safe and should be attempted for diagnostic and therapeutic purposes. Fluid from pancreatic pseudocysts is of low cellularity and is not inflammatory in nature.
Pancreatic pseudocysts can be treated medically or surgically. Medical management of pancreatic pseudocysts involves ultrasound-guided percutaneous aspiration and close monitoring of the size of the pseudocyst. Surgical intervention should be considered in cases in which clinical signs persist or when the size of the pseudocyst does not decrease significantly over time. Surgical correction can involve extirpation of the pseudocyst, with external or internal drainage; internal drainage is the preferred method in human patients.
Pancreatic abscess is a less common possible complication of pancreatitis. Bacterial infection is only rarely present. Clinical signs are non-specific but may include vomiting, depression, abdominal pain, anorexia, fever, diarrhoea and dehydration. In some patients a mass in the cranial abdomen can be identified upon abdominal palpation. Associated clinicopathological findings are similar to those of pancreatitis. Surgical drainage and aggressive antimicrobial therapy are the treatments of choice in human patients. However, in one report only five of nine dogs survived the immediate postsurgical period. Thus, given the mixed results, risks, difficulties and expense associated with anaesthesia, surgery and postoperative care, surgical intervention may be best avoided unless there is clear evidence of an enlarging mass and/or sepsis in a patient that is not responding well to medical therapy. Antimicrobial therapy is of questionable value unless an organism is identified upon bacterial culture.
In many patients with a single episode of pancreatitis, the only long-term therapy recommended is to avoid feeding high fat meals. In other patients, repeated bouts of pancreatitis occur and it may be beneficial to feed a fat-restricted diet permanently. In some patients hypertriglyceridaemia may need to be controlled pharmacologically. Despite all efforts, some animals experience recurrent disease.
Some reports have indicated that oral pancreatic enzyme supplements decrease abdominal pain and discomfort that accompanies chronic pancreatitis in human beings. It is unknown whether they are of similar value in dogs and cats, but a trial period of enzyme therapy may be warranted in individuals with chronic signs of abdominal pain or anorexia.
Pancreatitis is unpredictable and varies widely in severity; thus, it is difficult to give a prognosis even when a diagnosis is definitively established. Life-threatening signs accompanying acute fulminating pancreatitis are usually followed by death in spite of supportive measures but some dogs recover fully following an isolated severe episode. In other cases, relatively mild pancreatitis persists despite all therapy and either the patient dies from an acute, severe exacerbation of the disease, or is euthanized because of failure to recover or long-term cost. Most patients with uncomplicated pancreatitis probably recover spontaneously after a single episode and do well as long as high fat content foods are avoided.