Insulinoma is often described as a tumour of the pancreatic cells in the islets of Langerhans. It is best defined by the over production of insulin. The most common canine islet cell tumour affects the insulin-secreting beta cell. These beta cells comprise almost 70% of the cells located in the islets of Langerhans (Hess, 2010). Beta cells are primarily stimulated by an increase in circulating glucose, triggering the release of insulin. The islets of Langerhans also contain hormone producing alpha and delta cells. During times of hypoglycaemia the alpha cells release the hormone glucagon to antagonise or stop the release of insulin.
Although rare, insulinomas are most commonly seen in canine companions and rarely in felines. Signalment is not specific to a breed or gender, but has been mostly reported in older, medium to large breed canines (Hess, 2010). In contrast insulinoma is the most common neoplasm seen in pet ferrets (Pilney and Chen, 2004). Interestingly, 90% of insulinomas found in the human population are benign, but canine insulinoma has been shown to be predominately malignant (Fossum, 2002). A review of three studies compiling 179 dogs revealed a 45–64% rate of metastasis in canines with insulin secreting tumours. Metastasis was typically seen within the lymph nodes and liver, although there have been reports of metastasis to other organ systems (Hess, 2010).
Presentation
Patients typically present with an unremarkable physical examination. Most commonly owners will report episodes of ataxia, weakness, and disorientation with symptoms often resolving after a meal (Hess, 2010). Occasionally, hypoglycaemia may be detected during routine blood work analysis where the patient has yet to exhibit symptoms. A quick impulse to administer intravenous dextrose to non-clinical patients should be avoided as there is a potential for a delay in diagnosis. Dextrose administration may stimulate the tumour to release more insulin leading to a refractory hypoglycaemia (Armstrong, 2006). A list of diseases that may cause hypoglycaemia is provided in Table 1.
| Disease | Cause | Treatment |
|---|---|---|
| Sepsis/Sirs | Altered carbohydrate metabolism may lead to excessive glucose consumption exceeding production, multi organ dysfunction syndrome (MODS), hepatic dysfunction | Intravenous dextrose is used to stabilise the patient while searching for underlying disease process |
| Hypoadrenocorticism ‘addison's disease’ | Absence of glucocorticoids and/or mineralocorticoids affecting patient's ability to regulate blood glucose and electrolyte levels leading to shock | Intravenous dextrose and fluid therapy initially. Glucocorticoids are administered on suspicion of disease. Mineralocorticoids are administered on confirmation of disease |
| Insulin overdose (diabetic) | Accidental/Iatrogenic insulin overdose, transient diabetic/newly diagnosed diabetic | Intravenous dextrose to stabilise then monitoring and dose adjustment as needed |
| Toxin ingestion (xylitol) | Xylitol increases insulin secretion in dogs leading to hypoglycaemia | Intravenous dextrose to stabilise, monitor blood glucose and liver values until stable |
| Paraneoplastic syndrome | Cancer is thought to produce hormones creating endocrine-like effects such as hypoglycaemia and hypercalcaemia | Intravenous dextrose to stabilise while searching underlying disease process |
| Glycogen storage disease/toy breed hypoglycaemia | Patient is unable to regulate glucose during periods of fasting due to small size or congenital problem | Intravenous or oral forms of dextrose/food to stabilise |
| Hunting dog syndrome | Exercise depletes glucose stores during periods of fasting | Intravenous or oral forms of dextrose/food to stabilise. Meals should be fed before hunt and every 2–4 hours during |
Diagnosis
Laboratory tests
A tentative diagnosis is routinely confirmed by running a serum insulin level on blood that is sampled when the patient's glucose is less than 3.5 mmol/litre. If hyperinsulinaemia (>20 µU/ml) is present with hypoglycaemia (<3.5 mmol/litre) (reference range 2.5–4.2 mmol/litre) (Plumb, 2008) further diagnostics should be performed (Dunn et al, 1992). It is important that the sample is retrieved prior to administering intravenous dextrose. Patients with insulinoma will display high levels of insulin in a hypoglycaemic state consistent with a diagnosis for insulinoma (Armstrong, 2006). The turnaround time for this test can be lengthy and medical management must be instituted while awaiting results. Some patients may not exhibit hypoglycaemia without a period of fasting (48–72 hrs). Close monitoring in the hospital with blood glucose measurements may be beneficial. Blood fructosamine levels can also be submitted in euglycaemic canines with a high suspicion for insulinoma (Hess, 2010).
Imaging
Diagnostic imaging is primarily performed to rule out metastatic disease before pursuing surgical excision of the tumour (Fossum, 2002). A retrospective review of several studies utilising abdominal ultrasonography in 87 dogs with insulinoma revealed unreliable results. In these studies 56% of dogs displayed a pancreatic mass while 20% of dogs also revealed abdominal metastasis. Ultra-sonography alone can be an unreliable tool yielding both false-positive and false-negative results. If bloodwork is indicative of insulinoma, a computed tomography (CT) scan for pre-surgical screening to plan for surgical excision of the tumour can be considered (Hess, 2010). Human research has not provided an optimal imaging tool for insulinoma, but indicates high quality CT seems most effective. Although not widely available, intraoperative intraduct ultrasonography has been shown to reveal smaller (1–3 mm) tumours in humans (Tucker et al, 2006). One study comparing the use of ultrasound, CT and single photon emission CT in 14 dogs revealed a 71% accuracy of CT identifying an insulinoma. Despite these new findings intraoperative localisation is still a superior diagnostic technique (Robben et al, 2005). Advanced diagnostic tools utilising radioactive synthetic somatostatin followed by whole body scintigraphy have been utilised in human studies (Modlin et al, 1995), but studies utilising dogs as a model for this diagnostic tool have had unreliable results (Lester et al, 1999; Garden et al, 2005). The application of Whipple's triad (Table 2) can assist with a tentative diagnosis for insulinoma in the veterinary patient (Fossum, 2002). Interestingly, insulinoma was commonly diagnosed in humans utilising laboratory results and the presence of Whipple's triad alone, leading patients to surgery without perioperative localisation (CT, MRI). Identification of the location of insulinoma within the pancreas is desirable prior to surgery because this has been shown to reduce morbidity and mortality in humans (Okabayashi et al, 2013).
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Surgery
A surgical biopsy of the tumour would allow for both definitive diagnosis of insulinoma and staging of disease. As discussed in Fossum et al (2002) nearly 50% of all dogs that do not have evidence of metastatic disease at the time of surgery are normo-glycaemic for at least 1 year after partial pancreatectomy.
Prognosis
As previously stated, the incidence of malignancy and metastasis in canines is quite large. Many owners pursue surgery for pancreatectomy given the potential for remission. Although shorter survival rates were seen with liver metastasis, some of these patients recover without incident obtaining normo-glycaemia immediately. If patients are initially hyperglycaemic postoperatively they may nor-malise when previously supressed beta cells regain their function. Diabetes mellitus can also occur in about 10% of patients needing treatment with insulin (Hess, 2010). Pancreatitis is always a postoperative risk when handling this organ in surgery and care should be taken to monitor for occurrence (Fossum, 2002). If euglycaemia is not achieved with surgery alone medical management is indicated.
Medical management
Medical management of insulinoma may be uncomplicated or dynamic and critical. Intravenous access should be established to administer lifesaving dextrose if needed. Blood glucose monitoring and frequent meals (every 4 to 6 hours) can be utilised to maintain glucose levels until test results return and/or surgery is pursued. Ideally a dry diet high in complex carbohydrates and proteins should be fed. Canned diets may contain more simple sugars leading to hypoglycaemia (Fischer, et al, 2000). Glucose monitoring and dextrose supplementation is warranted pre-operatively while food is withheld prior to surgery (Fossum, 2002).
Glucocorticoid steroids have been shown to increase blood glucose concentrations by increasing gluconeogenesis and decreasing uptake into the tissues. Oral prednisolone (0.5–4 mg/kg/day) is cost effective and easily administered in patients able to take medication. Prednisolone should be started at the lowest possible dose and increased to effect. Dexamethasone sodium phosphate (0.5 mg/kg once daily to twice daily) can be administered intravenously in hospital if the patient is not tolerating oral medication (Hess, 2010).
Intravenous dextrose can be used to maintain euglycaemia (Figure 1). A dilute dextrose bolus (0.25–0.5 g/kg) prior to starting the patient on a 2.5% dextrose solution may suffice. A central line is useful for both venous access (serial glucose sampling) and hyperosmolar fluid administation. Serious phlebitis and vascular irriation can be seen in peripheral veins when dextrose concentrations exceed 5%. Blood glucose levels should be monitored every 2 hours or more frequently until the patient is stabilised (Reineke, 2012). Many cases can be managed with frequent meals, oral prednisolone and some intravenous dextrose supplementation (Hess, 2010).
Surgery is the treatment of choice where possible as it is associated with better prognosis when compared with medical management (Tobin et al, 1999); Polton et al's (2007) study strongly supports the role of prednisolone in the management of relapses after surgery, manifested by hypoglycaemia.
Long-term treatments
The lack of evidence-based literature specific to canine insulinoma has resulted in few and sometimes costly choices for patients. The most commonly used medication after prednisolone is diazoxide. A non-diuretic benzothiadiazide, it will block insulin by decreasing intracellular release of ionised calcium in the cells. This drug inhibits cellular uptake of glucose both directly and through the release of epinephrine. Side effects are usually dose dependent and can include vomiting, diarrhoea, in-appetence or tachycardia (Fischer et al, 2000).
Chemotherapeutic agents, such as streptozotocin, have been shown to work directly on the pancreatic beta islet cells effectively destroying them. Minor side effects include gastrointestinal distress, but there is also concern for liver and kidney dysfunction. Aggressive fluid diuresis during the infusion can be utilised to protect the nephrons and prevent damage to these organs (Fischer et al, 2000). Recent clinical trials utilising biweekly administration of streptozotocin versus the previously established 21 day protocol (Moore et al, 2002) to determine if better rates of hyperglycaemia could be achieved with minimal side effects were inconclusive. Further studies are needed to determine what role streptozotocin should play in the treatment of insulinoma (Northrup et al, 2013).
Somatostatins, naturally produced by the delta cells, have shown promise in human insulinoma, but have been inconclusive for canines. Octreotide, a long-acting somatostatin analogue, is said to block growth hormone, insulin and glucagon secretion (Simpson et al, 1995). Recent studies have shown octreotide decreases insulin and increases glucose plasma levels in dogs, but more studies are needed to determine the efficacy of octreotide use in canines with malignant insulinoma (Robben et al, 2006).
Refractory hypoglycaemia
The risk of cerebral injury in patients that display refractory hypoglycaemia becomes more concerning if the seizures cannot be controlled. Refractory hypoglycaemia is a condition in which the continued use of intravenous dextrose to maintain euglycaemia further triggers insulin release leading to a vicious cycle of hypoglycaemia. These patients may need dextrose concentrations greater than 5% to control hypoglycaemia. Unfortunately the hyperosmolar nature of these fluids may necessitate the placement of a central venous catheter to prevent venous phlebitis. It is advisable to consider a glucagon continuous rate infusion (CRI) if there is serious concern for refractory hypoglycaemia (Armstrong, 2006).
Novel therapies: glucagon CRIs
Glucagon pens are sold and labelled for treatment of hypoglycaemic crisis in people with diabetes. It should be noted that intravenous glucagon is contraindicated in people with insulinoma as it may cause refractory hypoglycaemia after initial hyperglycaemia (Lilly USA, 2012). There has been sporadic literature utilising glucagon intravenously and subcutaneously for management of canine insulinoma (Zeugswetter et al, 2012). A glucagon CRI can be made into a 1000 ng/kg/min solution and administered at rates of 5–13 ng/kg/min titrated to effect (Fischer et al, 2000). There is still a significant risk of rebound hypoglycaemia once the CRI is weaned. More evidence is needed to establish protocols utilising glucagon to stabilise refractory hypoglycaemia in canine patients.
Neurologic impact
Hypoglycaemia directly contributes to cellular swelling causing a cascade of events that can lead to cerebral oedema and cellular death. Mannitol, an osmotic diuretic, may be indicated in patients at risk for cerebral oedema. Furosemide, a loop diuretic, may work synergistically with mannitol to decrease intracranial pressure. If seizure activity persists, benzodiazepines (Table 3) may be utilised initially, although concerns do exist for patients with hepatic dysfunction. Anaesthetising the patient with propofol may be necessary if they continue to seizure. If needed these patients can be maintained on a propofol CRI. Although commonly utilised to control seizures, barbiturates (Table 3) may also interact with concurrent medication (i.e. prednisolone) causing negative side effects (Loose et al, 2008). More recently available medications such as levetiracetam have come into favour with relatively few side effects and drug interactions. Levetiracetam has minimal hepatic metabolism making it a better choice in patients with concurrent disease (Patterson et al, 2008).
| Drug | Class | Dose |
|---|---|---|
| Mannitol | Sorbitol isomer | 0.1 to 0.25 g/kg intravenously (IV) over 20 minutes with a filter |
| Furosemide | Diuretic | 0.75–1.0 mg/kg, IV |
| Diazepam | Benzodiazepine | 0.5–1.0 mg/kg, IV in cats and 0.5–2.0 mg/kg, IV in dogs |
| Midazolam | Benzodiazepine | 0.05–0.5 mg/kg, IM or IV constant rate infusion 0.35 mg/kg/min, IV in dogs |
| Propofol | Sedative | 0.1–0.6 mg/kg/min IV |
| Pentobarbital | Barbiturates | 3–15 mg/kg, IV given to affect |
| Phenobarbital | Barbiturates | loading dosage, 12–16 mg/kg, IV, divided over 4 hours |
| Levetiracetam | Anti-epileptic drug | 60mg/kg loading dosage then 10-20 mg/kg TID |
Patients with insulinoma may display mild symptoms of weakness or lethargy quickly resolving after a meal. Some patients may escalate to hypoglycaemic seizures and collapse. The seizure threshold for hypoglycaemic seizures causing central nervous system signs has been documented as 1 mmol/litre (Loose et al, 2008). The natural mechanisms to maintain perfusion to the brain and central nervous system (CNS) supersede all other organ systems as the CNS can only utilise glucose for cellular metabolism. Secondary sources of energy (i.e. ketones) can be utilised for cellular metabolism in other organ systems within the body, but glucose is mandatory for brain function (Armstrong, 2006). Compensatory mechanisms are in place to continually provide the CNS with glucose for cellular metabolism (Table 4). Insulin is suppressed while glucagon signals the liver to release glycogen that in turn releases stored glucose. Secondarily the hormones nor-epinephrine and epinephrine are released preventing peripheral uptake of glucose, thus preserving it for use in vital organs. The epinephrines will also stimulate hepatic release of glycogen. In addition, after hours of hypoglycaemia, cortisol and growth hormones are released in the hope of suppressing insulin and promoting gluconeogenesis. Further intracranial compensation occurs during periods of hypoglycaemia with an increase of glucose transporters (GLUTS) and increased cerebral blood flow (Loose et al, 2008).
| Origin | Agonist | Antagonist | End result | |
|---|---|---|---|---|
| Insulin | Pancreatic beta (β)cells | High blood glucose | Norepinephrine: i.e. stress response Glucagon Hyperglycaemia | Insulin + glucose = energy for cellular metabolism |
| Glycogen | Liver | Glucagon | Hyperglycaemia | Glycogen releases stored glucose |
| Glucagon | Pancreatic | Low blood glucose | Hypoglycaemia | Glucogenesis Glycogenolysis Inhibits insulin |
Conclusion
Although rare, canine insulinoma should always be considered in patients that present with sub-clinical hypoglycaemia. The dysfunctional beta cells in the tumour can create dangerously low blood glucose levels. The unfortunate rate of metastasis in these patients tends to leave owners with some difficult options. Treatment and stabilisation may lead to life-threatening refractory hypoglycaemia while awaiting confirmation of diagnosis and planning treatment. Despite the high rate of metastasis, many owners still choose to pursue surgical resection and medical management for their pets. Careful blood glucose monitoring and dextrose administration is a mainstay of treatment, but cerebral protective measures may need to be instituted if the patient becomes refractory. Novel and controversial therapies can be used to stabilise these patients, but the owners must be aware of the inherent risk involved with these treatments. Continued research establishing treatment protocols for canines diagnosed with insulinoma will be needed to improve on current treatment plans.