Surgical Diseases of the Endocrine Pancreas

Anatomy

The pancreas is a lobulated structure adjacent to the duodenum that consists of a body and two lobes or limbs. The body lies adjacent to the pylorus, whereas the right limb is closely associated with the descending duodenum on its dorsomedial aspect, enclosed by the mesoduodenum. The left limb of the pancreas lies between the peritoneal layers of the deep leaf of the greater omentum. It is caudal to the stomach and found dorsally in the abdomen adjacent to the left kidney and transverse colon.

The blood supply to the majority of the pancreas originates from the celiac artery via the hepatic and splenic arteries. The gastroduodenal branch of the hepatic artery gives off the cranial pancreaticoduodenal artery, which supplies the body of the pancreas and the cranial half of the right limb. The splenic artery supplies branches that enter the distal end of the left limb. The caudal pancreaticoduodenal artery originates from the cranial mesenteric artery and supplies the remainder of the pancreas. Innervation of the pancreas is derived either from the vagus and splanchnic nerves or is intrinsic to the gland [1].

Physiology of the Endocrine Pancreas

The endocrine function of the pancreas stems from specialized cells of the islets of Langerhans. These islets are ovoid collections of cells scattered throughout the parenchyma of the pancreas, making up a small portion of the pancreatic volume compared with the exocrine portion.2,3 The origin of islet cells is believed by some to be neuroectodermal, however this theory is controversial.4-6 Islet cells are functionally grouped as amine precursor uptake and decarboxylation (APUD) cells.2 These cells concentrate the amino acid precursors of certain amines and decarboxylate them to form the amines, which function as regulators and neurotransmitters. Functional tumors arising from these cells are termed APUDomas.

The cells of the islets are further categorized based on their hormonal production. Four distinct cell types have been described, each secreting a single hormone: A cells (alpha), B cells (beta), D cells (delta), and F (or P) cells [2,7]. A cells surround the centralized B cells and produce glucagon [2,8]. B cells secrete insulin and account for 60% to 75% of the islet cell population [2,9]. They are located within the center of the islet [2]. D cells produce somatostatin and occupy an intermediate position within the islet between the A and B cells. F cells secrete pancreatic polypeptide and are found in low numbers [9].

Disorders of the endocrine pancreas are usually a result of either an excess or deficiency in production of one of these hormones. Knowledge of the normal actions of each of these hormones, and the clinical signs and significance of their inappropriate production, is vital to understanding diseases of the endocrine pancreas. Diseases related to excessive or deficient production of insulin are the most common disorders of the endocrine pancreas.

Insulin

The main metabolic function of insulin is to regulate serum glucose concentration and promote the conversion of glucose, fatty acids, and amino acids to their storage forms (glycogen, triglycerides, and protein). The stimulus for insulin release from B cells is high serum glucose concentration. Insulin is made in the rough endoplasmic reticulum of the B cells and is then packaged in the Golgi apparatus into membrane-bound granules. The granules move to the plasma membrane via a process involving microtubules, and their contents are then expelled through exocytosis [2]. Other stimuli for insulin release include other sugars (fructose, mannose, ribose), amino acids, hormones (glucagon, secretin, gastric inhibitory peptide, cholecystokinin, growth hormone, adrenocorticotropin (ACTH), progesterone, and estrogen), drugs, fatty acids, potassium, acetylcholine, and ketones [2]. Glucose enters cells via facilitated diffusion or by secondary active transport with sodium (Na+) (intestine and kidneys) [2]. Insulin facilitates glucose entry into cells by increasing the number of glucose transporters in the cell membrane, particularly in muscle, fat, and some other tissues.2 Glucose penetrates only a few tissues readily, such as the brain, liver, and red and white blood cells.

Insulin facilitates glucose utilization via glycolysis and promotes glycogen production in the liver, adipose tissue, and skeletal muscle by increasing glycogen synthase activity. Insulin also decreases gluconeogenesis because of the promotion of protein synthesis in peripheral tissues, thereby decreasing the amount of amino acids available for gluconeogenesis [2].

In adipose tissue, insulin functions to increase glucose entry, fatty acid synthesis, glycerol phosphate synthesis, triglyceride deposition, and potassium uptake [2]. It also activates lipoprotein lipase and inhibits hormone-sensitive lipase. In muscle, insulin increases glucose entry, glycogen synthesis, amino acid uptake, protein synthesis in ribosomes, ketone uptake, and potassium uptake. It decreases protein catabolism, and release of gluconeogenic amino acids. In the liver, insulin increases protein and lipid synthesis, decreases ketogenesis, and decreases glucose output owing to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysis [2].

Glucagon

Glucagon is primarily a counter-regulatory mechanism hormone that restores plasma glucose levels in states of hypoglycemia by increasing gluconeogenesis, glycogenolysis, and protein-lipid flux in the liver [10]. It has an additional function in gastrointestinal smooth muscle relaxation [10].

Somatostatin

Somatostatin inhibits the secretion of islet hormones, including insulin, glucagon, and pancreatic polypeptide. It also inhibits the secretion of gut peptides, including gastrin and secretin. Finally, it inhibits pancreatic exocrine secretion and gastric acid secretion, and reduces splanchnic blood flow, intestinal motility, and carbohydrate absorption, while increasing water and electrolyte absorption [10].

Pancreatic Polypeptide

Pancreatic polypeptide reduces cholecystokinin-induced gastric acid secretion, increases intestinal transit times by reducing gastric emptying and upper intestinal motility, and inhibits postprandial exocrine pancreas secretion via a vagal-dependent pathway [10].

Specific Disorders of the Endocrine Pancreas

Diabetes Mellitus

Diabetes mellitus (DM) is the most common disorder of the endocrine pancreas in the dog and cat. Therefore, it is important for the surgeon to understand the anesthetic and perioperative management of the diabetic patient.

DM may be caused by failure of insulin production, failure of insulin release, excessive degradation of circulating insulin, or resistance to insulin effects by target tissues [11]. In people, DM is classified as type 1, type 2, gestational diabetes, and other specific types of diabetes [12]. Presently, no classification system exists for veterinary patients; however, the most common cause of DM in dogs and cats is failure of insulin production and secretion by the B cells of the pancreas. Type 1 diabetes in humans is characterized by B cell destruction leading to an absolute insulin deficiency.12 The cause of this destruction is usually a cellular-mediated autoimmune response [13]. Humans have multiple genetic predispositions to autoimmune destruction of B cells. B cell destruction in humans is also related to environmental factors that are still poorly defined [13]. The cause of B cell destruction in dogs and cats is unknown, however, evidence supports a role for immune-mediated processes. Inflammatory cell infiltration of pancreatic islets occurs in 46% of dogs with DM [14]. Anti-beta cell antibodies have been found in approximately 50% of dogs with insulin-dependent diabetes mellitus [15]. Islet cell destruction secondary to pancreatitis has also been proposed as a cause of diabetes mellitus. The pancreas has a large functional reserve, however, and progressive destruction of pancreatic tissue by recurrent or chronic pancreatitis is a rare cause of exocrine pancreatic insufficiency and diabetes in dogs [16].

When surgery is considered in a diabetic patient, the status of the patient’s diabetes must be determined and the goals of the surgery should be considered.11 Ideally, surgery should be delayed until the diabetes is well regulated. This is not always possible, however,as occasions may arise in which an urgent condition necessitates surgical intervention before diabetes can be regulated, or a patient’s previously well-regulated state may become disrupted owing to the onset of a new condition. The benefit of surgery must be weighed against the risk of pursuing it with the patient in an unregulated state. Surgery may be elective and independent of the diabetes itself, it may be part of long-term management of the diabetic state, or it may be emergent [11].

Pathophysiology

In diabetes mellitus, the deficiency of or resistance to insulin results in an inability to maintain a euglycemic state. Glucose transport into cells fails and despite high levels of glucose in the bloodstream, an intracellular glucose deficiency results: “starvation in the midst of plenty.” [2]. This state of starvation leads to inappropriate signaling by cells to increase hepatic gluconeogenesis and glycogenolysis, and decrease glycogenesis. Glycogen stores are quickly depleted and the liver signals for alternate substrates for glycolysis. Energy requirements can only be satisfied by using protein and fat reserves. Lipolysis of fat stores begins and fatty acids are metabolized, leading to the production of ketone bodies. The fatty acids are catabolized to acetyl-coA. The supply of acetyl-coA exceeds the capacity of the tissues to catabolize the acetyl-coA and the excess is converted to ketone bodies [2]. Muscle proteins are catabolized to amino acids for gluconeogenesis. The net effect of accelerated protein catabolism is a negative nitrogen balance, protein depletion, and wasting.

Diabetic patients may be complicated surgical patients owing to the various effects of their persistently hypoinsulinemic state. These patients may suffer from hepatic lipidosis because of excessive fatty deposition in their livers from mobilization of fat stores as a substitute glucose source [2,17]. Fatty acids are transported to the liver and the triglyceride depot is expanded. At the same time, insulin deficiency decreases the release of triglycerides from the liver, leading to hepatic lipidosis and hepatomegaly. This is often a problem in poorly regulated patients, but even well regulated diabetic patients may still have compromised hepatic function. This will have bearing upon anesthetic protocols, and dosages for anesthetic agents metabolized by the liver may need to be reduced [18].

Pancreatitis is another potential and serious consequence of diabetes [19-21]. Many diabetic animals are prone to pancreatitis and may have a history of it. Anesthesia and manipulation of the pancreas can cause hypotension and subsequently result in decreased perfusion of the pancreas, leading to an acute bout of pancreatitis upon the patient’s recovery [18,21]. This will complicate the management of the patient postoperatively and the need to withhold food from that patient will complicate the clinician’s ability to regulate the diabetes.

Although rare, diabetic nephropathy is an additional complication that may occur [22]. Histologic findings include membranous glomerulonephropathy, glomerular and tubular basement membrane thickening, glomerular fibrosis, and glomerular sclerosis. Severe proteinuria develops followed by azotemia, and eventually, uremia. Oliguric and anuric renal failure may ensue. The histopathologic findings are dependent on duration of the disease and control of hyperglycemia [22]. Other concurrent endocrinopathies may complicate management. Hyperadrenocorticism and acromegaly contribute to insulin resistance and may be causes for poor regulation of patients with diabetes mellitus.

Increased susceptibility to bacterial infections is a concern for the diabetic surgical patient [23]. Prolonged hyperglycemia predisposes to infection, and risk of infection may increase with increasing glucose concentrations [23,24]. Defective function of polymorphonuclear leukocytes has been demonstrated in diabetes mellitus [23,25]. Chemotaxis, phagocytosis, serum opsonic activity, and bactericidal function of neutrophils of diabetic patients are all diminished. Abnormalities in antibody formation, complement system, and cell-mediated immunity also have been found in poorly controlled diabetic patients [25]. Perioperative antibiotic therapy is advisable in diabetic patients.

Preoperative Evaluation of the Diabetic Patient

A thorough diagnostic evaluation should be completed prior to any surgical procedure in a diabetic patient. A thorough history and physical examination are essential. A minimum data base, including a complete blood count, serum chemistries, urinalysis and urine culture, is essential to identify concurrent problems. Urine culture should be performed owing to the susceptibility of diabetic patients to urinary tract infections. Evaluating the skin for evidence of dermatitis is important for identifying potential sources of infection that should be resolved prior to surgery. Radiographs, electrocardiogram, ultrasound examination, etc., should be completed prior to surgery if indicated based on history, physical examination findings and laboratory analysis. If the determination is made that the patient is poorly regulated, elective surgical procedures should be postponed until appropriate control of the diabetic state is attained.

Perioperative Management of the Diabetic Patient

Management during surgery requires special attention. If the animal’s disease is well regulated, food is withheld after midnight the night before the surgical procedure, and blood glucose concentration is measured on the morning of surgery. If the blood glucose concentration is greater than 150 mg/dl, one half of the regular dose of intermediate- or long-acting insulin is administered [26]. If the blood glucose concentration is less than 150 mg/dl, insulin is not given and the blood glucose concentration is re-evaluated postoperatively. Transient hyperglycemia is much less dangerous than hypoglycemia. Intravenous fluids containing 2.5% or 5% dextrose are started at induction and administered throughout anesthesia at 10 ml/kg/hour, unless there are indications to adjust this rate. For procedures of less than 1 hour, blood glucose can be measured postoperatively. Patients that have longer procedures and patients that are less well controlled should have their blood glucose concentration measured every 30 minutes. The dextrose drip should be adjusted as needed to prevent hypoglycemia. If the blood glucose concentration drops below 100 mg/dl, the rate of the dextrose drip (or its concentration for patients at risk of fluid overload) should be increased. If the blood glucose concentration is greater than 300 mg/dl, then 0.25 units/kg of regular insulin is administered subcutaneously.

Postoperative management is aimed at returning the patient to a normal routine and eating habits. Blood glucose concentration is measured every 4 to 6 hours with the goal of maintaining it between 150 and 250 mg/dl. If it increases above 250 mg/dl, regular insulin may be administered subcutaneously. A small meal should be offered the evening of surgery. Fluid therapy is continued overnight and if the patient eats the following morning, fluids are discontinued and the normal intermediate-acting insulin regimen is re-instituted. Transient hyperglycemia and glucosuria may occur for a few days after discharge from the hospital. The owner should be notified of this and advised not to change the insulin dose.

Unregulated or ketoacidotic diabetic patients requiring emergency procedures should be assessed via immediate evaluation of blood glucose concentration with reagent strips, hematologic and biochemical analysis, and urinalysis. Blood gas analysis is ideal if available. Appropriate stabilization with fluid therapy and correction of ketoacidosis is vital to restore acid-base and electrolyte balance and to counteract dehydration. Regular insulin is administered following guidelines of an established protocol for diabetic ketoacidotic patients. The goal is to lower the blood glucose concentration to less than 300 mg/dl and resolve ketonuria. The animal may exhibit Kussmal breathing as it attempts to blow off carbon dioxide and compensate for its metabolic acidosis. This should be recognized, particularly when the animal is under anesthesia, and not be mistaken for too light a plane of anesthesia. Falsely interpreting this breathing pattern and increasing the depth of anesthesia can have adverse consequences. Timing of surgery is determined by the patient’s response to therapy and the nature of the emergency. Gradual restoration of imbalances is best tolerated rather than attempting to normalize them all at once.

Ovariohysterectomy in the Diabetic Patient

Intact female dogs are especially prone to becoming unregulated as estrogen concentrations rise during proestrus and estrus and directly antagonize the effects of insulin. During the long luteal phase of diestrus, progesterone predominates and stimulates growth hormone secretion [27]. Growth hormone causes a decrease in the number of insulin receptors on target cell membranes and may also lower the affinity of the remaining receptors for insulin.11 This leads to prolonged and possibly severe insulin resistance. The animal is at higher risk for developing ketoacidosis as well as a uterine infection. Intact diabetic females are at risk for pyometra owing to the elevated progesterone concentrations and increased susceptibility to infection. The diabetic patient should undergo ovariohysterectomy before beginning her next estrus. If the patient presents in a ketoacidotic state, ovariohysterectomy may prove to be urgent in order to successfully control the diabetes. Postoperatively, insulin resistance will improve and the patient’s insulin requirements may markedly decrease. Careful serial monitoring of blood glucose concentration should be done.

Pregnancy also can disrupt the diabetic patient’s regulated state. Again, high concentrations of progesterone and growth hormone lead to insulin resistance. The placenta and fetus increase the demands for energy and hyperglycemia persists, possibly leading to ketoacidosis. Increased fetal growth hormone may lead to large feti which can cause dystocia and necessitate emergency cesarean section in an unregulated diabetic patient. The feti may also develop fetal beta-cell hyperplasia owing to high circulating levels of glucose, plasma amino acids, and fats from the poorly regulated mother.11 If they are carried to term, puppies and kittens may be prone to hypoglycemic seizures. It should also be recognized that the mother’s insulin requirement will decrease by 50% when the placenta separates from the uterus if a cesarean section is performed. Owing to the difficulties with blood glucose regulation associated with the estrous cycle and pregnancy, the increased susceptibility to developing pyometra, and the possibility of passing on diabetes mellitus to offspring, all intact females with diabetes should be spayed.

Pancreatic Transplantation for Treatment of Diabetes Mellitus

Pancreatic transplantation as a means of treating diabetes mellitus has been investigated for 4 decades. Whole pancreas transplantation has been successfully performed in dogs exclusively for research purposes. The first pancreatic transplantation in a human was performed in 1966. The major goal of transplantation is prevention or reduction of long-term complications of diabetes (such as heart disease, renal failure, blindness, and stroke). Successful transplantation appears to stop the progression of diabetic nephropathy and diabetic neuropathy; however, it requires major surgery and potentially lifelong immunosuppression to prevent rejection of the transplant [28]. The value of pancreatic transplantation in diabetic pets is problematic because diabetic dogs and cats do not live long enough (even with normal life expectancy) to develop the long-term complications seen in people. Ethical considerations are also a factor because one donor dog would have to be euthanized to provide a healthy pancreas for one recipient. Owners may find the side effects of immunosuppression more difficult to deal with than daily insulin administration. However, as technology improves, pancreatic transplantation may become a more viable option for pets.

Transplantation of pancreatic islets is a promising alternative to whole pancreas transplantation. Donor tissue can be altered to reduce immunogenicity, cost is moderated, and a larger number of patients can be treated. However, many islets must be transplanted because the duration of graft survival can be correlated with the number of islets transplanted [28,29]. This often requires utilization of several donors, which may lead to a need for levels of immunosuppression that can be harmful to the recipient [28]. This has led to the development of immunoprotected islet transplantation through microencapsulation. This process completely encloses each islet within a semipermeable membrane made of a nontoxic polysaccharide that is permeable to small molecules such as insulin and glucose, but is completely impermeable to large molecules such as immunoglobulins. This makes them "invisible" to the recipient’s immune system. Microencapsulated pancreatic islets have been transplanted free into the peritoneal cavity of 12 pet dogs with naturally occurring diabetes mellitus. Blood glucose concentration decreased to normal or below normal within 8 to 12 hours. Euglycemia was present for 1 to 6 months, with a mean of 3 months [28].

Insulinoma

The most common tumor of the endocrine pancreas in the dog is insulinoma, a functional tumor of the pancreatic beta cell. Insulinoma is diagnosed in middle-aged to older dogs (average age 9 years, range 3-15 years).30 It occurs primarily in large breed dogs including Irish setters, Labrador retrievers, German shepherds, and golden retrievers. No gender predilection is associated with insulinomas in dogs [31]. Insulinoma is considered rare in cats as few cases have been reported [32-34]. Of these reports, all cats were of older age (range 12-17 years) and 3 of 5 were Siamese.

Pathophysiology

Insulinomas secrete insulin independently of the normal suppressive effects of hypoglycemia. Although insulin is the most abundant hormone produced by these tumors, evidence exists of multihormonal production, including pancreatic polypeptide, glucagon, somatostatin, serotonin, and gastrin [35,36]. Clinical signs associated with insulinomas result from the hypoglycemic effects of hyperinsulinemia, leading to neuroglycopenia, and stimulation of the sympathetic nervous system, leading to an increase in circulating catecholamines [30,37,38]. Clinical signs caused by neuroglycopenia include lethargy, weakness, ataxia, collapse, seizures, posterior paresis, and depression [13, 34]. Clinical signs resulting from stimulation of the sympathoadrenal system include muscle tremors, nervousness, restlessness, and hunger [37,38]. Clinical signs are usually episodic because of the counter-regulatory mechanisms that enable recovery from hypoglycemic episodes [38]. Clinical signs can be present for days to months, with most dogs being symptomatic for 1 to 6 months prior to presentation [30,38]. The onset of clinical signs is related to the degree of hypoglycemia and the rate at which it occurs [30,38]. Gradual blood glucose changes are less likely to cause clinical signs of hypoglycemia than an acute drop. Dogs that have a slowly decreasing glucose concentration over a prolonged period of time (i.e., weeks) may be able to adjust without showing clinical signs until the blood glucose concentration reaches a point at which the animal can no longer adapt to the hypoglycemia and signs of neuroglycopenia result [38]. These dogs can typically adjust to blood glucose concentrations as low as 20 to 30 mg/dl. However, if the hypoglycemia develops acutely, perhaps over a few hours, clinical signs will develop quickly. Because of the failure of insulin secretion to drop during periods of hypoglycemia, dogs with insulinoma are predisposed to developing clinical signs during fasting and exercise [38]. In addition, insulin-secreting tumors remain responsive to many of the stimuli that promote insulin secretion in healthy dogs, such as eating, but the secretory response may be exaggerated, so severe hypoglycemia can occur [38].

Normally, B cells of the pancreatic islets maintain the primary control of blood glucose concentrations. When blood glucose concentration rises above 110 mg/dl, insulin is secreted and the glucose concentration decreases into the normal physiologic range. When the blood glucose concentration falls below 60 mg/ dl, insulin synthesis and secretion are inhibited and blood glucose returns to normal as tissue utilization slows and blood glucose concentration increases [38]. With insulinoma, insulin secretion is not inhibited and hypoglycemia results. Hypoglycemia triggers the production of counter-regulatory hormones including glucagon, epinephrine, growth hormone, and cortisol. Glucagon, epinephrine, and norepinephrine concentrations increase at the onset of the counter-regulatory response; growth hormone and cortisol increase later [38]. Glucagon is the main counter-regulatory hormone in acute hypoglycemia. Glucagon secretion is stimulated by hypoglycemia and by beta-adrenergic nervous system stimulation and adrenomedullary catecholamines [38]. Glucagon is secreted into the portal circulation and activates glycogenolysis and gluconeogenesis in the liver. Hypoglycemia stimulates growth hormone secretion, which decreases glucose uptake into some tissues, increases hepatic production of glucose, and possibly decreases tissue binding of insulin.2 Adrenocorticotropic hormone and cortisol are increased by direct stimulation of the pituitary gland and stimulation of the pituitary-adrenocortical axis by the sympathetic nervous system. Long-term elevation of cortisol aids lipolysis, promotes protein catabolism and the conversion of amino acids to glucose by the liver and kidney, and limits utilization of glucose by tissues. The effects of increased cortisol and growth hormone do not occur for hours and are more effective in countering chronic hypoglycemia than acute hypoglycemia. The autonomic nervous system response to hypoglycemia has alpha- and beta-adrenergic effects. Hypoglycemia stimulates catecholamine secretion by the adrenal medulla. Alpha-adrenergic effects result in inhibition of endogenous insulin secretion and stimulation of peripheral vasoconstriction, causing an increase in cerebral blood flow in the healthy dog. Epinephrine stimulates hepatic glycogenolysis and gluconeogenesis, mobilizes muscle glycogen and gluconeogenic precursors, stimulates lipolysis, and inhibits glucose utilization by insulin-sensitive tissues. Beta-adrenergic effects include stimulation of hepatic and muscle glycogenolysis, increased plasma glucagon secretion, stimulation of lipolysis, inhibition of glucose uptake by muscle, and increased cerebral blood flow secondary to an increase in cardiac output. Cholinergic effects lead to stimulation of pancreatic polypeptide secretion, increased gastric motility, and hunger stimulation [38]. The counter-regulatory response to hypoglycemia can be effective in controlling hypoglycemia; however the continued production and secretion of insulin from an insulinoma will eventually overwhelm the ability of these mechanisms to counteract the hypoglycemia. Without surgical or medical intervention, the patient will succumb to the effects of hypoglycemia.

Hypoglycemia can affect most cells, but the cells of the central nervous system (CNS) are the most vulnerable. The carbohydrate storage ability of these cells is minimal and glucose is their primary energy source. A continuous supply of glucose from the blood is essential. Glucose enters the cell via diffusion, independent of insulin. When the blood glucose concentrations are inadequate for intracellular oxidative processes, a decline in energy-rich phosphorylated compounds (adenosine triphosphate [ATP]) occurs in neurons [38]. The lack of energy results in cellular dysfunction and cellular changes similar to hypoxia: increased vascular permeability, vasospasm, vascular dilation, and edema. This is followed by neuronal death [11,38]. Owing to varying metabolic rates in the CNS, the most active sites are affected first. In mammals this is the cerebral cortex. The least metabolically active area is the brainstem and, therefore, it is more resistant to hypoglycemia [11,38]. The majority of damage occurs in the brain, but peripheral nerve degeneration and demyelination can occur [38]. Other major organ systems are dependent on glucose for energy, but the CNS will show signs of an acute drop in blood glucose long before organ failure develops [38].

Differential and Definitive Diagnosis

A thorough diagnostic workup must be performed to make a diagnosis of insulinoma. This begins simply with an accurate and thorough history from the owner as well as a thorough physical exam. A patient-side glucose test strip should be run at presentation, but results of serum chemistries will help most in identifying hypoglycemia as the primary or sole cause of the clinical signs. Hypoglycemia is defined as a blood glucose concentration below 60 mg/dl. The presence of hypoglycemia narrows the differential list, but does not establish insulinoma as the cause. Whipple’s triad has classically been used as a criterion for diagnosis: (1) presence of neurologic signs associated with hypoglycemia, (2) fasting blood glucose concentration below 60 mg/dl, (3) resolution of clinical signs with feeding or administration of glucose [38-40]. Whipple’s triad however only confirms hypoglycemia as the cause of the neurologic signs. It does not yield a diagnosis of insulinoma, because any cause of hypoglycemia could fulfill Whipple’s triad [38-39,41].

Hypoglycemia results from excessive glucose utilization, impaired hepatic gluconeogenesis and glycogenolysis, deficiency of counter-regulatory hormones, inadequate dietary intake of glucose and/or its substrates, and iatrogenic hypoglycemia [38]. Hepatic-induced hypoglycemia can be a result of congenital causes such as portosystemic shunts or acquired causes such as cirrhosis and acquired portosystemic shunting. Insufficient hepatic glycogen stores and inadequate hepatocellular function to support gluconeogenesis are responsible for the hypoglycemia associated with liver disease [38]. Any severe insult to the liver that results in decreased hepatocellular function, such as infection, toxic insult, or necrosis, can lead to hypoglycemia. Hypoglycemia can be caused by starvation or sepsis, or may be idiopathic in neonates, toy breed dogs, and hunting dogs [42]. Endocrinopathies such as adrenocortical insufficiency, hypopituitarism, ACTH deficiency, glucagon deficiency and non-beta cell-derived hyperinsulinism can cause hypoglycemia. Glycogen-storage disease, renal failure, cardiac disease, and polycythemia are also associated with hypoglycemia. Artifactual hypoglycemia can occur from prolonged blood storage prior to separation of the red cells from the serum or plasma. Continuing metabolism of glucose by the red blood cells will decrease the glucose concentration in a whole-blood sample. Iatrogenic hypoglycemia can occur owing to insulin or oral sulfonylurea drug overdosage. Finally, extrapancreatic neoplasia, such as leiomyosarcoma and hepatic adenocarcinoma, has been associated with hypoglycemia. Hepatic tumors may grow large enough that they utilize a large amount of glucose as well as interfere with gluconeogenesis. These tumors can also secrete insulin and insulin-like peptides that contribute to hypoglycemia. Often, patients with hypoglycemia not associated with hyperinsulinism will have other clinical pathologic abnormalities that will help to narrow the differential diagnosis list and guide further diagnostics.

The diagnosis of insulinoma is supported by finding an inappropriately elevated serum insulin concentration in the presence of hypoglycemia. The insulin concentration must be compared with the concurrent blood glucose concentration. The serum insulin concentration in a healthy fasted dog is usually between 5 and 20 μU/ml. Blood glucose concentration is normally between 70 and 110 mg/dl. A serum insulin concentration that exceeds 20 μU/ml in a dog with a blood glucose concentration less than 60 mg/dl, along with clinical signs, strongly supports the diagnosis of an insulin-secreting tumor [38]. However, an insulin-secreting tumor is also possible with a serum insulin concentration in the high normal range (10–20 μU/ml). Animals with other causes of hypoglycemia as well as those with insulin-secreting tumors may have a serum insulin concentration between 5 and 10 μU/ml. In 85 dogs with blood glucose concentrations less than 60 mg/dl, 73% had a serum insulin concentration greater than 20 μU/ml, 21% had a serum insulin concentration between 10 and 20 μU/ml, and 6% had a concentration between 5 and 10 μU/ml [38]. Several different insulin:glucose ratios have been used to further assess the likelihood of an insulin-secreting tumor. Although these ratios are controversial, the amended insulin:glucose ratio is considered to be the most reliable[38]. The amended insulin:glucose ratio consists of the following formula:
plasma insulin (µU/ml) x 100
plasma glucose (mg/dl) – 30

Based on the human literature, an amended insulin:glucose ratio greater than 30 is diagnostic for an insulin-secreting tumor. However, in dogs this test is not specific for insulinoma. Other causes of hypoglycemia, such as hepatic tumors and sepsis, may result in abnormal amended insulin-glucose ratios [38]. Because of this, the absolute serum insulin concentration during hypoglycemia should be evaluated in concert with the history, physical examination findings, and clinical pathologic test results [38,39].

Provocative tests, including the glucagon tolerance test, l-leucine test, tolbutamide and ethanol response test, oral glucose tolerance test, epinephrine stimulation test, calcium infusion test, C-peptide suppression test, and diazoxide infusion test, have been reported [11,38,39]. These tests are not considered more sensitive than the insulin-glucose pair, can be expensive and inefficient, and can potentiate significant hypoglycemia dangerous to the animal, so they are not recommended.

The disease process is further characterized with diagnostic imaging. Abdominal radiographs are usually unremarkable owing to the small size of insulinomas and their location within the pancreas; a visible mass or visceral displacement is extremely rare [38]. Although metastasis can occur to the liver, lymph nodes, and peripancreatic omentum, these lesions are not likely to be detectable on radiographs. Pulmonary metastasis is rare, and thoracic radiographs are usually unremarkable until late in the disease. Abdominal ultrasonography is likely to be more useful than radiography, but can still be unrewarding. Detection of a mass in the pancreas is helpful in supporting a diagnosis of insulinoma in animals that have the appropriate clinical picture. It is common to be unable to identify a lesion in the pancreas and, therefore, the lack of an identifiable mass via ultrasonography does not rule out its presence. Ultrasonography may also detect metastatic lesions in the liver and peripancreatic tissue.

The use of computed tomography (CT) for identifying insulinomas has recently been investigated. In one study of 14 confirmed insulinomas, ultrasonography, CT, and single-photon emission CT (SPECT) were evaluated for detecting and localizing canine insulinoma [43]. Five primary insulinomas were correctly identified with ultrasonography, 10 with CT, and 6 with SPECT [43]. CT identified 2 out of 5 lymph node metastases, but also showed 28 false-positive lesions [43]. The authors concluded that ultrasonography could be used for initial evaluation of dogs with hypoglycemia, and although CT identified most primary tumors, intraoperative inspection and palpation were still superior. SPECT appeared as effective as ultrasonography and CT [43]. Scintigraphy has also been used as an additional imaging modality. In one study, 5 dogs with insulinomas were imaged using [111] In-pentetrotide scintigraphy to identify somatostatin receptors. All insulinomas expressed high-affinity somatostatin receptors [44]. However, scintigraphy was able to accurately predict the anatomic location of the primary tumor in only 1 out of 4 dogs, and was unable to differentiate a right- from left-pancreatic lobe tumor [44,111]. In-pentetrotide scintigraphy was concluded to be a useful diagnostic adjunct but was unable to localize the tumor in some cases 44.

Treatment

Surgical exploration of the abdomen offers the best results in terms of diagnosis, therapy, and prognosis. Most dogs with insulin-secreting tumors have visible nodules present upon inspection of the pancreas [38]. Definitive diagnosis is based on histopathologic evaluation of lesions resected or biopsied at the time of surgery. A solitary nodule within the pancreas is likely to be resectable and will afford long-term control of hypoglycemia, however, cure is unlikely. The goal of surgery is to remove as much neoplastic tissue as possible; debulking of gross metastatic disease may afford a significant therapeutic effect. The blood glucose concentration should be stabilized as well as possible prior to anesthesia and surgery. Manipulation of an insulinoma may result in release of insulin and a further drop in blood glucose concentration.

Localization of a pancreatic mass is based on careful inspection and gentle palpation of the entire pancreas. Primary lesions are distributed equally between the two limbs of the pancreas, and an identifiable mass was located approximately 92% of the time in one source [38]. Another source reported inability to identify a mass in 20% of cases [45]. If a mass is not identified, special methods, such as intravenous administration of methylene blue and intraoperative ultrasonography, can be used to assist in identification of the lesion [46-48]. Methylene blue is an azo dye that concentrates in the parathyroid glands and endocrine pancreas. Intravenous infusion of this dye has been recommended for identification of primary nodules and differentiation of metastatic versus non metastatic lesions [46-48]. Methylene blue stains normal pancreatic endocrine tissue a dusky slate blue, whereas hyperfunctioning tissue is stained a reddish-violet [34]. Side effects include Heinz body hemolytic anemia, acute renal failure, pseudocyanosis, green-tinged urine, and possibly pancreatitis [46-49]. Intraoperative ultrasonography in humans has a success rate of greater than 95% for finding insulinomas; this modality may prove useful in dogs [50].

Thorough exploration of the abdomen is vital to identifying the extent of metastatic disease. Gross metastasis is identifiable at the time of surgery in approximately 36% of cases [51]. Metastasis most commonly occurs to the liver, regional lymph nodes, and peripancreatic tissue. Lesions should be biopsied or resected if possible. Ideally, all of the abnormal tissue should be removed and submitted for histopathologic evaluation.

Palpation may reveal a thickened pancreas, or the pancreas may feel completely normal.

Successful surgery depends on the location of the tumor. A tumor in the left or right limb at the distal aspect is the most amenable to resection. Tumors at the body or in the region of the common bile duct are the most difficult to remove and increase the risk of postoperative pancreatitis owing to the potential for disrupting pancreatic blood supply. The extensive manipulation necessary to remove tumors in this area and the likelihood of incomplete resection may warrant a decision to leave the mass. If non resectable disease is present, biopsy of the mass is the minimum the surgeon should accomplish. Closing the abdomen and pursuing medical therapy is advisable.

Intravenous fluids should be administered for 12 to 24 hours prior to, during, and after surgery to ensure adequate perfusion of the pancreas. Manipulation and dissection of the pancreas during surgery results in inflammation and predisposes the animal to postoperative pancreatitis. Hypotension will result in poor perfusion of the pancreas and may potentiate pancreatitis. Aggressive fluid support may help avoid hypotension and minimize the severity of the pancreatitis. Dextrose therapy is often needed to counteract clinical signs of hypoglycemia. Administration of a 2.5% or 5% dextrose solution is usually adequate. Maintenance of normal blood glucose concentration intraoperatively is extremely important. It should be measured every 30 to 60 minutes during surgery with a goal of maintaining it above 40 mg/dl, but not to necessarily reach a normal blood glucose concentration. It is rare to need more than a 5% dextrose solution, and if needed, a constant rate infusion of glucagon can help raise the blood glucose concentration when dextrose alone is inadequate.

Postoperative care is aimed at controlling pancreatitis, hypoglycemia, and if it occurs, hyperglycemia. Serum electrolytes and blood glucose concentration should be measured twice daily. If pancreatitis is recognized, intravenous fluid therapy is continued (routinely 120 ml/kg/day) and food and water are withheld for 24 to 48 hours. Plasma administration is advisable and parenteral nutrition is started.

If persistent hypoglycemia occurs postoperatively, functional metastatic disease is present. Medical therapy to prevent clinical signs should be instituted as well as frequent feeding (every 4 to 6 hours) with a diet appropriate for pancreatitis. Feeding frequency is increased to at least 3 to 6 times per day. A variety of medical therapies can help to control hypoglycemia. Glucocorticoid therapy (prednisone or prednisolone 0.25 mg/kg PO every 12 hours) is often the first medication used when frequent feedings are not adequate. The glucocorticoid dose can be increased as needed to control clinical signs, keeping in mind the adverse side effects of this drug. Increasing doses of glucocorticoids will result in signs of hyperadrenocorticism and possibly gastric ulceration. When these side effects become unacceptable, the glucocorticoid dose should be decreased and another therapy added to control the clinical signs of hypoglycemia.

Diazoxide (5 mg/kg PO every 12 hours) is a benzothiadiazide that is used alone or in combination with glucocorticoids. Diazoxide inhibits insulin secretion, promotes hepatic gluconeogenesis and glycogenolysis, and inhibits tissue use of glucose. Diazoxide can be difficult to obtain and is expensive. It is reported to be 70% effective in controlling hypoglycemia but does not have any antineoplastic effects [52]. The dose can be increased to 30 to 40 mg/kg PO every 12 hours if necessary. Side effects include hyperglycemia, bone marrow suppression, cardiac arrhythmias, hypernatremia, cataracts, and gastrointestinal disturbances [52,53].

Octreotide is a somatostatin analog that inhibits insulin secretion and has been used with varying success in humans [54,55]. Doses up to 40 μg every 8 to 12 hours are reported to be effective without causing adverse side effects [56]. In one study, the endocrine effects of a single subcutaneous dose of 50 μg of octreotide were studied in healthy dogs in the fasting state and in dogs with insulinoma. After octreotide administration to dogs with insulinomas, baseline plasma insulin concentrations decreased significantly and plasma glucose concentrations increased [57]. However, evaluation of octreotide in a study of 3 dogs with insulinoma showed that octreotide had no benefit over placebo and little effect on circulating glucose and insulin concentrations [58].

Streptozocin is a nitrosurea alkylating agent that is directly cytotoxic to pancreatic beta cells. It had previously not been advisable to use in dogs owing to its association with acute renal failure from renal tubular necrosis [59-61]. Other side effects are vomiting, which can be severe, and increases in hepatic enzyme activities. These toxicities are dose-dependent, with vomiting and hepatic enzyme increases occurring at lower dosages. Acute renal tubular necrosis occurs at higher doses. A diuresis protocol has met with some success [62]. Normal saline was administered at 18.3 ml/kg/hour intravenously for 3 hours prior to streptozocin administration. The dose (500 mg/m2) was diluted to the appropriate volume and administered over the next 2 hours at the same rate. Normal saline was then administered for another 2 hours after the streptozocin infusion was complete. Butorphanol (0.4 mg/kg IM) was given as an antiemetic immediately after streptozocin administration. Treatments were repeated every 3 weeks until there was no evidence of tumor progression (> 50% increase in tumor dimensions), recurrence of hypoglycemia, or development of a streptozocin-induced toxicosis. Mean duration of euglycemia was 163 days compared with 90 days for the control group, although this was not statistically significant. Two dogs had measurable reductions in size of metastases, and the clinical signs of 2 of 3 dogs with polyneuropathy resolved. Side effects of the drug were minimal with the diuresis protocol [62].

Prognosis

Long-term prognosis for insulinoma in dogs is guarded to poor owing to the malignant behavior of these tumors. They are malignant in terms of their metastatic potential; microscopic or gross metastasis at the time of diagnosis is almost certain. Mean survival time from the onset of clinical signs has been reported to be 12 months for dogs treated medically [63]. However, Tobin reported a median survival time of 74 days for dogs treated medically and a median of 381 days for those that underwent surgery.64 It should be noted that the medically treated dogs had advanced disease and may have had shorter survival times because of this and the owners’ possible feelings of hopelessness leading to euthanasia. Prognosis also depends on age at the time of onset of clinical signs, with younger dogs having significantly shorter survival times than older dogs. Dogs that have a solitary pancreatic nodule (stage I) have significantly longer disease-free intervals (mean 14 months) after surgery than those with metastatic spread to the liver, regional lymph nodes (stage II), or distant sites (stage III) [65]. High preoperative serum insulin concentrations are also associated with shorter survival times [65]. Approximately one third of dogs undergoing surgery die or are euthanized within 1 month as a result of severe metastatic disease, uncontrollable hypoglycemia, or postoperative pancreatitis. Another one third die or are euthanized within 6 months of surgery owing to severe metastatic disease and recurrence of clinical hypoglycemia. The final one third live beyond 6 months without recurrence of hypoglycemia and many of these survive well beyond 1 year [63].

Gastrinoma (Zollinger-Ellison Syndrome)

Gastrinomas are pancreatic islet cell tumors that secrete excessive amounts of gastrin. They were first identified in humans in 1955 by Zollinger and Ellison[66]. The Zollinger-Ellison syndrome consists of hypergastrinemia, a neuroendocrine tumor, and gastrointestinal ulceration. These tumors are rare in veterinary patients with only a few reports in the literature [67-70]. They occur in middle-aged dogs (range: 3-12 years, mean 7.5 years) and older cats (mean 11 years)[38]. No breed predilection has been identified. Female dogs and cats may be overrepresented [71].

The most common clinical signs of gastrinoma are vomiting, anorexia, and weight loss owing to gastroduodenal ulceration [9,23,67-69]. Other signs that may occur include lethargy, depression, hematemesis, hematochezia, diarrhea, melena, and abdominal pain. These animals are at risk for gastrointestinal perforation and peritonitis from the ulcerative disease, and may experience collapse and shock secondarily. Physical examination may be unremarkable or may reveal an extremely sick animal if perforation has occurred [9,30,67-69]. Physical examination findings depend on the severity and duration of disease. Animals may be lethargic, thin to emaciated, febrile, dehydrated, and in shock [3].

Pathophysiology

Gastrin is a polypeptide hormone produced by G cells in the lateral walls of the glands of the antral portion of the gastric mucosa [2]. It is also found in the pancreatic islets in fetal life. Gastrinomas are found in the pancreas, but it is uncertain if gastrin is found in the pancreas in normal adults [2]. The main actions of gastrin are stimulation of gastric acid secretion and pepsin secretion, as well as stimulation of the growth of gastric mucosa and small and large intestinal mucosa [2].

The stimulus for gastrin secretion is related to the contents of the stomach, with secretion increased by the presence of the products of protein digestion (amino acids) that act directly on G cells. Luminal distention is also a stimulus for gastrin secretion. Gastrin inhibition occurs via the direct effect of acid in the antrum on G cells and by release of somatostatin, a gastrin-secretion inhibitor [2]. In patients with gastrinoma, hypergastrinemia induces excessive gastric secretion of hydrochloric acid, which is responsible for the development of esophageal, gastric, and duodenal ulcers, the disruption of intestinal digestive and absorptive functions, and the development of clinical signs[38]. With excessive gastrin secretion, hydrochloric acid secretion is increased and this hyperacidity leads to ulceration. Reflux esophagitis may occur, and as the excessive acid moves through the GI tract, it can cause direct ulceration of the duodenum and jejunum. Intestinal hyperacidity may also lead to intestinal inflammation, mucosal edema, villous atrophy, and inactivation of pancreatic lipase and bile salts [38,72]. Gastrinomas may also secrete other hormones including insulin, ACTH, and pancreatic polypeptide.

Diagnosis

Diagnostic workup includes a minimum database consisting of a complete blood count, serum chemistries, and urinalysis. CBC abnormalities seen with gastrinoma include neutrophilia, hypoproteinemia, and regenerative anemia, likely resulting from inflammation and blood loss. Serum chemistry abnormalities may include hypoalbuminemia, hypocalcemia, and increases in alanine aminotransferase and alkaline phosphatase. Hypochloremia, hypokalemia, and metabolic alkalosis may occur from frequent vomiting. Tumor secretion of other hormones such as ACTH and insulin may occur and possibly lead to hyper- or hypoglycemia. Sudan staining of fecal material may reveal steatorrhea; melena is usually present. Urinalysis is unremarkable.

Abdominal radiographs are usually unremarkable. However, if an ulcer has perforated, loss of abdominal contrast consistent with peritonitis may be present. Contrast radiography can identify gastric and duodenal ulcers and thickening of the gastric rugal folds, pyloric antrum, and/or intestine[38]. Increased gastrointestinal transit time as well as esophagitis and secondary megaesophagus may be present. Abdominal ultrasonography may find thickened gastric and intestinal walls, gastric ulcers, a pancreatic mass, and/or metastatic lesions[38]. Gastrinomas can be difficult to identify because of their potentially small size; failure to identify a mass by ultrasonography does not rule it out. Scintigraphy with radiolabeled somatostatin analogues may be useful owing to a high concentration of somatostatin receptors in gastrinomas in people [70]. A positive scan can also help identify patients that may benefit from medical therapy with somatostatin analogues like octreotide, which decrease gastrin release [67-70].

Gastroduodenoscopy may reveal ulcerative lesions in the stomach and duodenum as well as esophagitis. Gastric rugal folds may be thickened. Histologic evaluation of the gastric mucosa may reveal mild to severe inflammation with lymphocytic, neutrophilic, eosinophilic, or plasma cell infiltrates as well as mucosal hypertrophy.

Definitive diagnosis of gastrinoma is based on histopathologic and immunocytochemical evaluation of the mass excised at surgery. Baseline serum gastrin concentrations are useful prior to surgical exploration, particularly if a pancreatic mass is not visualized by ultrasonography. Demonstration of persistent hypergastrinemia with appropriate clinical signs is supportive of a diagnosis of gastrinoma. Fasting serum gastrin concentration is measured with multiple blood samples drawn after an overnight fast. The reference range for gastrin concentration will vary among laboratories, but the upper limit is usually less than 100 pg/ml in dogs and cats [70,73]. The majority of reported cases of histologically confirmed gastrinoma in dogs and cats have gastrin concentrations greater than three times higher than the upper normal value. Normal gastrin concentrations have been documented in humans with gastrinoma, and so it is likely that dogs and cats with normal gastrin concentrations may still have a gastrinoma. It is also important to note that an elevated fasting serum gastrin concentration is not pathognomonic for gastrinoma. Other syndromes associated with hypergastrinemia include chronic renal failure, chronic gastritis, gastric outflow obstruction, liver disease, achlorhydria, and administration of H2-receptor antagonists[38]. Once hypergastrinemia is documented and other causes are ruled out, a presumptive diagnosis of gastrinoma can be made.

Treatment

Treatment is aimed at surgical excision of the tumor and control of gastric acid hypersecretion. The decision as to when exploratory surgery is performed depends on the clinical status of the animal. Prior to undertaking anesthesia, the animal must be stabilized. Medical therapy with gastric acid blockers should be instituted first with the goal of reducing gastric hyperacidity and controlling its secondary effects. Surgical goals include identification of a pancreatic mass and definitive diagnosis, as well as successful resection of the tumor. Because approximately 80% of animals with gastrinomas have gastrointestinal ulcers, the stomach and bowel should be evaluated for evidence of deep or perforated ulcers, and resection of these areas should be performed when necessary [7]. Surgery also offers an opportunity to stage the disease by identifying and biopsying gross metastatic lesions. Approximately 70% of animals have metastasis at the time of initial diagnosis [38].

Medical therapy for gastrinomas involves blocking gastric acid hypersecretion with H2-receptor antagonists and the H+-K+ ATPase inhibitor, omeprazole. For maximal hydrochloric acid secretion from parietal cells to occur, three receptor sites must be activated. These receptor sites bind gastrin, histamine, and acetylcholine. H2-receptor antagonists bind to the H2-receptor and block gastrin’s stimulatory effect on hydrochloric acid secretion because all three receptor sites are not occupied by their respective peptides[38]. H2-receptor antagonists include famotidine (0.5 – 1.0 mg/kg PO every 12-24 hours), ranitidine (2.2 mg/kg PO every 12 hours) and cimetidine (10 mg/kg every 6-8 hours). Dosages may need to be increased as the disease progresses to control hyperacidity.

Omeprazole is the preferred drug for gastrinoma in humans[38]. It acts as a proton pump inhibitor (inhibits parietal cell H+-K+ ATPase), which is the last common step in gastric acid secretion. Omeprazole is considered to be more effective than H2-receptor antagonists because it inhibits gastric acid secretion stimulated by any of the secretagogues, while the H2-receptor antagonists inhibit only the actions of histamine. Omeprazole has a long duration of action and is effective at controlling the clinical signs of gastrinoma in dogs [73]. Dosage is 0.7 to 1.0 mg/kg PO every 24 hours.

Octreotide, a long-acting somatostatin analogue, is occasionally used in humans with gastrinoma refractory to H2-receptor antagonists and omeprazole. It has been used in dogs.70 Dosing ranges between 5 to 20 µg subcutaneously every 8 hours.

Prognosis

The long-term prognosis for gastrinoma is poor owing to its highly malignant nature with 76% of cases having gross metastasis at the time of diagnosis [74]. In previous studies, surgical and/or medical treatment resulted in survival times of 1 week to 18 months [75]. With the availability of drugs to reduce gastric hypersecretion and to promote healing of ulcers, the short-term prognosis is improving.

Glucagonoma

Glucagonoma is a tumor of the A cells of the pancreatic islets in which excessive amounts of glucagon are inappropriately secreted. Glucagon-secreting tumors are rare in both humans and animals, with only a few reported cases in dogs [76-82]. Dogs typically present with a characteristic dermatitis involving the foot pads that is consistent with superficial necrolytic dermatitis (SND). High levels of glucagon are thought to be involved in the development of these skin lesions, although the mechanism is poorly understood. Patients may also develop diabetes mellitus caused by stimulation of gluconeogenesis and glycogenolysis from excessive secretion of glucagon [76]. DM usually occurs when insulin production cannot match the increased glucagon secretion [77]. Other clinical signs include cheilosis, normocytic-normochromic anemia, venous thrombosis, weight loss, polyuria, polydipsia, glossitis, stomatitis, and diarrhea. Three dogs with glucagonoma ranged in age from 8 to 11 years and had a chief complaint of chronic dermatitis. Skin lesions occur particularly in areas of trauma and involve hyperkeratosis of the foot pads; erythematous, erosive, and crusting lesions on the muzzle, external genitalia, perineum, and periocular region. Other common historical complaints included weight loss, polydipsia, and polyuria. Weight loss is likely a result of the catabolic effects of glucagon on fat and protein metabolism [83].

Diagnosis

A baseline complete blood count, serum biochemistries, and urinalysis should be obtained. Clinical pathologic abnormalities can include a mild nonregenerative anemia, hypoalbuminemia, hepatic enzyme elevations, low blood urea nitrogen, and possibly persistent hyperglycemia. Elevated serum glucagon concentration in the absence of hypoglycemia is suggestive of the presence of a glucagonoma [38,80]. Other syndromes associated with mildly elevated glucagon concentrations include diabetic ketoacidosis, renal failure, hepatic failure, sepsis, and starvation [30]. Hypoaminoacidemia may also be a feature of this disease, and supplementation of amino acids may improve dermatologic conditions [30]. Skin biopsies are necessary to diagnose superficial necrolytic dermatitis, which is characterized by diffuse parakeratotic hyperkeratosis, acanthosis, vacuolar changes of keratinocytes, and epidermal edema [76-79]. Submission of multiple biopsy samples from the edges of early skin lesions is most useful [80]. Diagnostic imaging of the thorax and abdomen may show evidence of local or metastatic disease. Abdominal ultrasonography may reveal hepatic lesions or a pancreatic mass, however, of 9 dogs with glucagonomas that had ultrasonography performed, a pancreatic mass was visualized in only one dog [76-82]. Abdominal computerized tomography has been used in one dog to identify a pancreatic mass and was also successful in identifying multiple liver masses [77].

Treatment and Prognosis

Surgical resection is the treatment of choice. Histologic evaluation of pancreatic masses in dogs has demonstrated pancreatic carcinomas with glucagon immunoreactivity [77-79]. Metastasis is common, and if present, tumor debulking may be helpful in palliating clinical signs. Chemotherapy has been attempted in humans with some success [84-85]. Dietary supplementation with essential fatty acids, zinc, and amino acids may improve skin lesions, and has shown success as an infusion in one case report in a man [86]. Long-term prognosis is poor. Most canine patients are diagnosed late in the course of the disease, preventing the possibility of a cure. Short-term palliation of signs can be successful with early surgical and medical treatment.

Pancreatic Polypeptidoma

Pancreatic polypeptide (PP) is a common component of pancreatic islet cell tumors. It is well documented that the majority of endocrine tumors contain multiple hormones, and pancreatic polypeptide is the second most common hormone identified by immunocytochemistry in canine pancreatic endocrine tumors [87]. This rare pancreatic islet cell tumor has been documented to produce clinical signs in only one dog. This 7-year-old spayed female cocker spaniel presented with a history of chronic vomiting, anorexia, and weight loss [87]. Elevated serum PP concentration was documented. Serum gastrin concentrations were also elevated but provocative testing was normal. Necropsy revealed a pancreatic adenocarcinoma with metastasis to the liver, gastric hypertrophy, and multiple duodenal ulcers. Immunocytochemical staining of the tumor for gastrin was negative. Serum PP concentrations were extremely elevated and both the tumor and its metastases stained strongly positive for PP. The authors proposed that the high serum concentrations of PP contributed to the dog’s gastrointestinal ulceration and vomiting [87].

VIPoma and Somatostatinoma

VIPomas are pancreatic islet cell tumors that have been identified in humans, but have not been documented in dogs and cats [38]. Intestinal secretion of fluid and electrolytes secondary to high circulating concentrations of vasoactive intestinal polypeptide (VIP) causes clinical signs of profuse watery diarrhea, fecal loss of potassium and bicarbonate, and low or absent gastric acid secretion. This may lead to a severe metabolic acidosis secondary to bicarbonate loss in the diarrhea. VIPomas are diagnosed based on measurement of serum fasting VIP concentrations by radioimmunoassay and histologic confirmation of a non-beta-cell pancreatic tumor with a high content of VIP [88]. Surgical excision is the treatment of choice, with 50% achieving remission when metastasis is not present [89]. Medical therapy with streptozocin plus fluorouracil has been used in humans with non resectable or metastatic carcinoma. Octreotide has been used to lower plasma concentrations of VIP in patients refractory to other treatment modalities.

Somatostatinomas have also been recognized in humans, but not in dogs and cats. Somatostatin has been found to be present in canine islet cell tumors [32,35,36]. In humans, excess secretion of somatostatin from D cells of the pancreas causes glucose intolerance, cholelithiasis, diarrhea, steathorrhea, hypochlorhydria, and weight loss [90]. Diagnosis is based on clinical features, documentation of increased serum concentrations of somatostatin, and histologic examination of the tumor. Metastasis occurs to the liver and adjacent lymph nodes and is usually present at the time of diagnosis of these slow-growing tumors. Surgical excision is the treatment of choice, but chemotherapy with streptozocin has been attempted [38].

Conclusion

The endocrine pancreas is a complex organ that presents multiple challenges for the veterinary surgeon. Its production of various hormones and their effects on the body require an understanding of the normal physiology of the endocrine pancreas as well as the pathophysiology of its disorders. These disorders can be challenging to diagnose and a thorough understanding of endocrine function is necessary to correlate the clinical picture with its etiology. Diagnosis and appropriate management of affected cases relies on knowledge of the mechanism of disease, the potential for perioperative complications, and the long-term outcome with medical or surgical management.