16.

PANCREATITIS
Pancreatitis is the most common exocrine pancreatic disease in both dogs and cats. It
can be acute or chronic, depending on whether the disease has led to permanent changes
of the pancreatic parenchyma, mainly atrophy and/or fibrosis. Both acute and chronic
pancreatitis can be subclinical, mild and associated with vague clinical signs, or severe
and
associated with pancreatic necrosis and systemic complications. The determination of
whether pancreatitis is acute or chronic can only be made definitively based upon a biopsy
and histopathological examination. The differentiation cannot be made upon clinical signs
alone.
Whilst acute pancreatitis can tend to be more severe, in some cases it is mild, and the
clinical signs with chronic disease can sometimes be severe. Thus a distinction between
the two is clinically of little significance.
Aetiology
In most cases of pancreatitis in dogs the aetiology remains undetermined. There are a
number of potential risk factors that have been identified however. Obesity has been
suggested as a risk factor for the disease, and the disease has been reported as less
severe when experimentally induced in lean dogs. Hyperlipidaemia, often grossly
recognised in patients with acute pancreatitis, may be the consequence of abdominal fat
necrosis, or may potentially induce the disease. In the case of Minature Schnauzers, there
is a possible link between the familial hyperlipidaemia and the apparent increased
incidence of pancreatitis.
Concurrent endocrinopathies (diabetes mellitus, hyperadrenocorticism, hypothyroidism),
and epilepsy have been considered risk factors.
There are a number of drugs that have been suggested as inducing agents of
pancreatitis, however definitive evidence to prove a causal link is often lacking.
Glucocorticoids were long implicated, but evidence to support this is lacking, other than
perhaps the very high dose regimes sometimes used for patients with spinal cord injury.
Other drugs that have been suggested as risk factors include chemotherapeutic drugs
(Lasparaginase, vinca alkalaoids), cytotoxic drugs (azathioprine), diuretics (frusemide,
thiazides), anticonvulsants (potassium bromide), antimicrobials (sulphonamides,
tetracyclines), and NSAID such as salicylates.
Some toxins have been associated with the disease, including cholinesterase inhibitors
or cholinergics. The theory is that they stimulate hypersecretion. Other toxins include zinc
and scorpion venom.
Hypercalcaemia has also been recognised as a cause of pancreatitis in dogs. This may
be spontaneous (malignancy, hyperparathyroidism, renal failure, hypoadrenocorticism,
granulomatous disease, destructive bone disease), or may be iatrogenic (vitamin D
toxicity).
Reflux of duodenal juice into the pancreatic duct can cause pancreatitis, but rarely
occurs in a normal patient because of the anatomy of the duodenal papilla, which has a
muscular sphincter and is also covered by a special piece of mucosa. It may be more likely
to occur after surgical intervention in the area, such as the formation of a closed duodenal
loop.
Obstruction of the pancreatic ducts typically results in pancreatic atrophy and fibrosis.
However if pancreatic secretion is stimulated inflammation may occur. Clinical causes of
pancreatic duct obstruction can include surgical manipulation of the area, neoplasia,
oedema of the duct or duodenal wall, a strategically located duodenal foreign body,
trauma, parasites, spasm of the sphincter, or biliary calculi.
Pancreatic trauma may induce pancreatitis. This may be the result of blunt abdominal
trauma, but may be iatrogenic with surgery.
Other potential causes of pancreatitis include ischaemia (associated with shock, or
hypotension), infectious agents (uncommon, but viral, parasitic and mycoplasmal causes
have been suggested, as has Babesia), or potentially immune mediated disease.
Pathophysiology
The basic mechanism of the disease is autodigestion of the pancreas. There are several
mechanisms in place in the pancreas to prevent this process. The first is that the digestive
enzymes (both proteolytic and phospholipolytic) are produced and then stored in an
inactive form in zymogen granules. The process of activation is achieved by the enzymatic
cleavage of a small activation peptide from the amino terminal of the polypeptide chain.
The activation typically occurs in the small intestine after secretion of the zymogens. The
duodenal enterocytes secrete an enzyme called enteropeptidase that is very effective at
cleaving the activation peptide from trypsinogen. The activated enzyme, trypsin, then
cleaves the activation peptide from the other zymogens. It is important to remember
though that enteropeptidase and trypsin are not the only enzymes that have the capability
to activate the zymogens. There are lysosomal proteases that have this capability.
A second mechanism is the strict separation of the digestive enzymes during synthesis,
storage and secretion from other cellular enzymes, including the lysosomal enzymes. The
digestive enzymes are stored in zymogen granules, separate from lysosomes. Calcium
also plays a role in enzyme activation, and it can have both an inhibitory and activating
role. At low concentrations (as in acinar cells), calcium binding protects trypsinogen
activating peptide from exposure. Whereas at higher calcium concentrations (as found in
the pancreatic duct and intestine), calcium increases the sensitivity of trypsinogen to
activation by trypsin.
Higher pH levels in the pancreas and ducts also minimise enzyme activation.
If adequate activation of the trypsin takes place within the pancreatic cells and ducts,
the other zymogens (including proelastase and prophospholipase) will be activated, further
increasing pancreatic damage. As further enzyme is activated within the pancreas, a mild
oedematous pancreatitis may progress to more severe haemorrhagic or necrotic disease,
and then more systemic signs of disease will manifest. If activated digestive enzymes gain
access to the vascular space, there are plasma protease inhibitors that are very important
in minimising their adverse effects, which may be fatal. If they are not bound the free
proteases will induce disseminated intravascular coagulation by activating the coagulation,
fibrinolytic, kinin and complement systems. In addition to the activation of the coagulation
and fibrinolytic systems, the activated enzymes stimulate the activity of numerous
inflammatory mediators. These include, but are not limited to tumour necrosis factor,
interleukins, interferon, nitric oxide, and platelet activating factor. It is these mediators,
along with systemic inflammation, that result in the systemic signs seen in some patients
with pancreatitis.
Clinical signs
Whilst any dog can be affected, middle aged and older and overweight dogs are more
commonly affected. The clinical signs will vary with the severity of the disease process. In
more severe cases common clinical signs may include anorexia, vomiting, weakness,
abdominal pain, diarrhoea, and obtundation. In some severe cases there may be more
systemic clinical signs including fever, tachypnoea or dyspnoea, or signs of shock.
Abdominal pain has not been reported as frequently in canine patients as in human
patients. The abdominal pain may be manifest by the assumption of an unusual posture
(prayer position), or a pain response upon physical examination.
Other physical examination findings may include the presence of a palpable cranial
abdominal mass, or evidence of a peritoneal effusion. Some patients may have respiratory
distress, icterus, dehydration, or signs of a bleeding disorder. Cardiac arrhythmias may
also be apparent. Some severely affected patients may be hypothermic.
Chronic pancreatitis, or milder acute pancreatitis may have less specific clinical signs,
and in some patients there may be no clinical signs at all. Therefore it is more likely that
the diseases may remain undiagnosed.
Diagnosis
Routine haematology and biochemical profile changes tend to be relatively nonspecific
in the diagnosis of the disease. A neutrophilia and left shift is a relatively common
finding in affected patients. Neutropaenia is occasionally noted. Thrombocytopaenia may
be noted in over 50% of cases, and may serve as an indicator for DIC. The PCV may be
elevated secondary to haemoconcentration, or may be reduced. A biochemical profile may
reveal azotaemia, which could be secondary to dehydration, or could indicate renal
damage and the onset of acute renal failure. Elevated liver enzymes may be the result of
bile duct obstruct ion, ischaemia, or the drainage of toxic material from the pancreatic
veins into the portal vein.
Hyperbilirubinaemia may occur for similar reasons to the hepatic enzymes.
Hyperglycaemia can be the result of elevated levels of cortisol, catecholamines and
glucagon, or damage to the endocrine pancreatic tissue. Some patients may become
diabetic. Hypoalbuminaemia may be the result of loss because of vasculitis or effusion.
Hypocalcaemia may be secondary to the hypoalbuminaema, or the formation of calcium
salts with fatty acids associated with fat
necrosis. Hypercholesterolaemia and hypertriglyceridaemia are commonly recognised.
Electrolyte and acid base abnormalities are frequently recognised, secondary to vomiting
and hypovolaemia.
Urinalysis is important in affected animals to aid in the interpretation of the
biochemical profile. The urine specific gravity may be elevated because of dehydration.
The presence of azotaemia and an inappropriately low specific gravity raises questions
about renal function. In the presence of acute renal failure there may be active urine
sediment present, with casts noted.
If DIC is suspected, coagulation parameters should be measured (prothrombin time,
activated partial thromboplastin time, D-dimers or fibrinogen degradation products).
Many non invasive tests clinical pathologic tests for the diagnosis of pancreatitis have
been evaluated and many have found to be of limited diagnostic value.
Serum amylase and lipase have long been used to confirm the diagnosis of canine
pancreatitis. However both have limited sensitivity and specificity. Whilst the pancreas
synthesises lipase, so do other tissues and the catalytic assay utilised does not
differentiate the source of lipase. Lipase elevations may occur with renal failure,
glomerulonephritis, hepatic disease, intestinal disease, the administration of
glucocorticoids (especially dexamethasone), or heat stress. The information for serum
amylase is very similar, with many non pancreatic sources. It is important to note that
about 50% of patients with an elevated serum amylase, lipase, or both do not have
pancreatitis.
The serum trypsinogen-like immunoreactivity test (TLI) detects trypsinogen and some
trypsin in the circulation, and is a species specific test. The test has proven to be very
specific for the diagnosis of EPI in dogs and cats. It was found that dogs with
experimentally pancreatitis had elevated TLI levels. Some dogs with spontaneous
pancreatitis will have an elevated TLI level, but this may be less than 40% of patients.
Sensitivity and specificity have been reported as 65% and 33% respectively, limiting the
diagnostic value. As discussed previously, one of the limitations of the catalytic assay for
lipase is that it does not differentiate the many sources of lipase in the body. The different
lipases do have different molecular structures. The gastrointestinal laboratory at Texas A
and M University purified classical pancreatic lipase (cPL) from dog pancreas, and
developed antisera against this in rabbits. Further testing demonstrated that the only cell
type staining positively for cPL was the pancreatic acinar cell, and a reference rangewas
developed using 74 clinically healthy dogs. A radiommunoassay and ELISA were
developed and validated, with the ELISA commercially available. The cPLI levels were
demonstrated to be reduced in dogs with EPI. The cPLI was evaluated in dogs with
chronic renal failure, and it was found that the levels were within reference ranges, and
promising results were obtained in patients with gastritis. The levels are not affected by the
administration of prednisolone. Another study compared the results of various diagnostic
tests in cases of biopsy proven pancreatitis. The sensitivity was shown to be over 80%.
Further evaluation may be necessary in patients with mild or chronic disease.
Abdominal radiography has the advantage of being freely available to almost all
practitioners. In patients with pancreatitis there may be a number of possible abnormal
findings. These may include an increased density, or a loss of detail in the abdomen, or a
granularity or ground glass appearance, especially in the right cranial quadrant. The
stomach may be displaced to the left, increasing the angle between the pylorus and
duodenum, and the descending duodenum may be displaced to the right. Gas
accumulation may be noted in the descending duodenum, with a suggestion of a thickened
duodenal wall, or there may be gas accumulation in the transverse colon with caudal
displacement. There may be gas accumulation in the stomach, and if barium is
administered there may be delayed transit through the stomach and duodenum, with an
irregularity of the duodenal wall. However none of the aforementioned findings are
definitive. Pleural effusion may be noted in a small number of dogs with severe disease.
Abdominal ultrasonography is a frequently used technique for diagnosis of acute
pancreatitis, but is not without limitations. There are well defined criteria for the diagnosis,
and if applied, the sensitivity is good (~70%). Pancreatic enlargement alone is not
diagnostic, because there can be other causes of pancreatic oedema, including portal
hypertension. Local effusion alone is also not diagnostic. Altered pancreatic echogenicity is
important. Decreased echogenicity may suggest oedema or necrosis, and the gland may
appear mottled. The pancreatic dimensions are variable. The surrounding tissue may be
hyperechoic, typically the inflamed mesentery with fat necrosis. Generalised or regional
effusion may be noted. The liver and biliary system should also be evaluated, especially if
the patient has elevated hepatic enzymes or icterus. Chronic pancreatitis may be
associated with increased echogenicity in the pancreas associated with fibrosis.
Advanced imaging options are available. Contrast enhanced CT is frequently used in
humans as a diagnostic tool. MRI may also have potential value. However both are
expensive and require general anaesthesia.
Pancreatic biopsy and histopathological examination is typically considered the gold
standard test for diagnosis. It is important to note that even this technique has its
limitations.
Studies have shown that pancreatic inflammation typically occurs in discrete areas within
the gland, rather than diffusely. There is also random distribution within the gland of the
inflammation. It may be possible that a single biopsy or even multiple small biopsies may
not identify inflammation. The presence of inflammation or necrosis is certainly diagnostic,
but their absence does not rule out the diagnosis. Biopsies can be obtained at laparotomy,
or laparoscopically. Biopsy is the only way to definitively classify pancreatitis as acute or
chronic.
Treatment
Fluid Therapy: Intravenous fluids are the mainstay of therapy for pancreatitis.
Initially fluids should correct dehydration over the first 12–24 hours, while also meeting
maintenance needs. The fluid rate should be adjusted frequently to account for ongoing
losses (e.g., vomiting, diarrhea, ascites) and to correct fluid, electrolyte and acid-base
imbalances. If needed, colloidal support can be given in the form of fresh frozen plasma,
hetastarch or dextrans (10–20 mL/kg/day). Plasma will provide a -macroglobulins to
scavenge activated proteases within the serum; it also provides clotting factors and is
indicated if there is evidence of disseminated intravascular coagulation (DIC). However,
human studies showed no improvement in the clinical course or mortality with plasma
administration.
Pain Management: Analgesic therapy should be considered for abdominal pain in
every animal with suspected or confirmed pancreatitis. Intravenous or subcutaneous
opioids are typically utilized while the patient is hospitalized. Alternatively, intraperitoneal
infusions of lidocaine or bupivacaine mixed with sterile saline can be administered.
Options for outpatient pain control include fentanyl patch, tramadol or butorphanol.
Nutritional Support: Although nutritional support for pancreatitis has been debated in
veterinary medicine, human literature recommends nutritional support. In uncomplicated
pancreatitis, the vomiting patient can be held NPO (fasting) for 24–48 hours with
subsequent gradual reintroduction of a low-fat diet when vomiting subsides. While NPO
does provide a “rest” for the pancreas, most veterinary patients have been anorexic for
>48 hours at the time of presentation, thus further withholding of nutrition is likely
detrimental. Alternatively, nutritional support can be provided by total parenteral nutrition
(TPN) or enteral nutrition (EN). Experts recommend enteral nutritional support in all
patients with pancreatitis. EN stabilizes the gut barrier, improves enterocyte health and
immune function, improves GI motility and prevents catabolism. Enteral nutrition can be
provided by a variety of feeding tubes, including nasogastric (NG) or nasoesophogeal (NE)
tubes, esophogostomy tubes, gastrostomy tubes or jejunostomy tubes. Jejunostomy tubes
bypass the pancreas and can be used in patients when vomiting cannot be controlled.
Endoscopically placed jejunostomy tubes have been described in dogs and provide an
opportunity for EN without prolonged anesthesia and surgery. While TPN will support the
rest of the body, the GI tract still starves as it receives nutrition from the intestinal lumen
Other Treatments: Other potential therapies for pancreatitis include antiemetics,
antacids, antibiotics and dopamine. Antiemetics will help control vomiting and allow for
earlier EN. Choices include ondansetron (Zofran®), dolasetron (Anzemet®),
metoclopramide and chlorpromazine. Antacids can either be an H2-receptor antagonist
(ranitidine or famotidine IV) or a proton-pump inhibitor (pantoprazole). Pancreatitis is
usually a sterile process in dogs and antibiotics are not indicated. Rarely, antibiotics may
be used if a pancreatic abscess is present or there is evidence of bacterial translocation
from the gastrointestinal tract. In research settings, dopamine at low doses (5 μg/kg/min)
maintains mesenteric blood flow and limits increased microvascular permeability.
Monitoring
During hospitalization, pancreatitis patients must be monitored closely as their status
can change rapidly. Electrolytes, acid-base status, azotemia, icterus and coagulation
status should be reevaluated regularly (e.g., every 24–48 hours in patients with severe
disease).
Abdominal ultrasound can be repeated intermittently to evaluate for the development of, or
changes in, pancreatic pseudocysts and/or abscesses. Spec cPL ® concentrations will fall
as pancreatic inflammation resolves and can be repeated as often as every two to three
days in severely ill, hospitalized patients to help determine if the pancreatitis is improving.
In more stable patients, the Spec cPL Test can be repeated every one to two weeks.
Long-Term Management
Chronic management of pancreatitis will vary depending upon the severity of the
disease. Single, acute, uncomplicated episodes may only warrant initially avoiding high-fat
meals with a return to a normal maintenance diet. However, patients with repeated
episodes of acute pancreatitis or evidence of chronic disease should be maintained on a
fat-restricted diet.
Drugs associated with pancreatitis (e.g., potassium bromide, L-asparaginase,
azathioprine, furosemide, tetracycline, aspirin, sulfa drugs) should also be avoided in these
patients. There is debate about supplementing oral pancreatic enzymes for patients with
chronic pancreatitis In a recent study, 57% of dogs followed six months after a single,
acute episode of pancreatitis had evidence of either ongoing inflammation (increased
cPLI) or decreased functional acinar cells (decreased TLI) despite resolution of symptoms.
Prognosis
Patient prognosis is guarded in many cases of pancreatitis. However, rapid diagnosis
and implementation of appropriate therapy early in the course of disease will reduce
patient morbidity and mortality. Once a predisposition for pancreatitis is identified, long
termmonitoring with the Spec cPL test may be warranted, especially if changes are made
todietary therapy and/or pancreatitis-predisposing drugs are used.