Current approach to insulinoma in ferrets (Proceedings)

Pancreatic islet beta cell tumors secrete high levels of insulin and cause hypoglycemia. Clinical signs include lethargy, weight loss, weakness, ptyalism, bruxism, seizures, and death. Treatment modalities include medical therapy, chemotherapy, surgery, and dietary changes. The etiology of insulinoma is unknown, however a nutritional hypothesis has recently been offered along with a prevention strategy based upon feeding a more natural, archetypal diet.

Epidemiology

Insulinoma is by far the most common neoplasm in ferrets, with a reported incidence of approximately 25% of neoplasms diagnosed. It is commonly seen in middle-aged to older ferrets. Although most affected ferrets begin exhibiting clinical signs around 4 years of age, it has been reported in ferrets as young as 2 weeks of age. It is likely that islet cell tumors exist subclinically for months or years before symptoms occur. Both sexes may be affected, but there are conflicting reports as to whether males are slightly overrepresented.

Insulinomas appear to occur regionally. They are uncommon among ferrets in Europe, New Zealand and Australia. The majority of ferrets from these areas are fed a low-carbohydrate diet of meat scraps, poultry scraps, and/or fish scraps, and sugary treats are not provided. By contrast, insulinoma is common in the United States, where the majority of ferrets are fed dry kibble containing 10-45% carbohydrate, and many are fed treats that contain sugar. Finkler hypothesizes that such excessive carbohydrate intake stimulates excessive insulin production by the pancreas and results in compensatory hyperplasia. He postulates that lifelong stimulation of pancreatic beta cells leads to a hyperinsulinemic "preinsulinoma" state and eventually to the development of beta cell neoplasia.

Domestic pet ferrets in the U.S. are supplied by a small number of breeders, thus limiting their genetic diversity, and suggesting that the development of insulinomas may have a genetic component.

Pathophysiology

The pancreas plays a major role in glucose, lipid, and protein metabolism through the balance of its two major hormones, insulin and glucagon. Insulin, a polypeptide produced by beta islet cells, is released when levels of glucose, amino acids, and free fatty acids are increased in the blood. In the case of a sudden increase in the blood glucose level, the plasma insulin level can increase almost 10 fold within minutes. Insulin then causes a rapid uptake of glucose into peripheral tissues and promotes the storage of glucose in the muscle and liver. Additionally, insulin inhibits hepatic gluconeogenesis and glycogenolysis, and promotes the conversion of excess glucose into fatty acids. The net effect of all these processes is a decrease in blood glucose levels. Glucagon is secreted by alpha cells in response to decreasing glucose levels and is involved in effects that are exactly opposite to those of insulin, namely, an increase in the blood glucose level.

Beta cell tumors produce their effects through the overproduction of insulin. Insulin is released when levels of glucose, amino acids, and free fatty acids are increased in the blood. Insulin then causes a rapid uptake and storage of glucose by cells, inhibits hepatic gluconeogenesis and glycogenolysis, and promotes the conversion of excess glucose into fatty acids. The net effect of all these processes is a decrease in blood glucose levels. Insulinomas secrete indiscriminately and are not responsive to inhibitory stimuli such as hypoglycemia or hyperinsulinemia. In addition, rapidly increasing levels, even in the presence of low blood glucose concentration, can stimulate excessive insulin release from these tumors, causing a profound rebound hypoglycemia. Although local tumor recurrence is common, metastasis to other organs is not. This finding is in contrast to insulinomas found in dogs, which are usually malignant and metastatic. When insulinoma metastasis does occur in a ferret, the regional lymph nodes, liver and spleen are the organs most commonly involved.

Clinical signs

Ferrets affected by insulinoma show signs of hypoglycemia, which may vary depending on the degree of hypoglycemia and the rate of glucose decline. Early signs are often slow and insidious in their development and are not easily recognized by the owner. Such signs include a reduction in activity, weight loss, and difficult arousal from slumber. Appetite may be normal or decreased.

As the disease progresses and hypoglycemia worsens, more significant clinical signs develop. These include anorexia, lethargy, mental dullness, irritability, tremors, stargazing, and a glassy-eyed appearance. Hypersalivation and pawing at the mouth (presumably due to nausea, numbness, or tingling) also occur. Because ptyalism is associated with nausea, other diseases such as gastric ulcers or foreign body should be ruled out. Affected ferrets may present with classic hindlimb paresis or ataxia, as if spinal damage has occurred. Corticosteroid injection, which raises blood glucose levels, may temporarily improve symptoms and sometimes thwarts the diagnosis.

Severely affected ferrets may present in a state of acute collapse, hypothermia, stupor, seizures, or coma. Signs of acute collapse, seizure, or unresponsiveness may be reversed temporarily with the application of dextrose solution, honey or corn syrup to the oral mucosa. Seizures may occur with less frequency in ferrets than in dogs due to the fact that most ferrets are fed ad libitum and have a low-activity lifestyle associated with cage restriction.

Clinical signs are often episodic, but the severity and frequency of clinical signs often progress if left untreated. Prolonged episodes of severe hypoglycemia can result in neuronal glucose deprivation and cerebral hypoxia, leading to subsequent lesions in the cerebral cortex.

Diagnosis

Insulinoma is often identified in asymptomatic ferrets during routine testing, or as part of the workup for a concurrent disease process. In patients were insulinoma is suspected but blood glucose is within normal limits (80-120 mg/dL), a carefully monitored 3- to 4-hour fast may be required to confirm hypoglycemia. A presumptive diagnosis is made when ferrets demonstrate fasting blood glucose of less than 60 mg/dL in the presence of clinical signs of insulinoma, and these signs cease after a feeding or intravenous administration of glucose (Whipple's triad). Other causes of hypoglycemia, such as sepsis, starvation, hepatic disease, and laboratory artifact should be systematically ruled out.

Immediate evaluation of freshly drawn blood with a handheld glucometer provides a quick relative assessment of the blood glucose status. However, most handheld point-of-care glucometers are not validated for ferrets and may report values that are 10-20 mg/dL lower than actual glucose levels. The AlphaTrak® blood glucose monitor (Abbott Animal Health) has been validated for use in ferrets and appears to yield reliable results.

Plasma or serum obtained during periods of hypoglycemia can also be submitted for insulin level. Normal insulin level for ferrets is 4.88-34.84 μU/ml (35-250 pmol/L). Elevated insulin level with concurrent hypoglycemia is consistent with hyperinsulinism and supports the diagnosis of insulinoma. However, a low or normal insulin level does not necessarily rule out the presence of insulinoma, and could indicate erratic insulin production.

Various insulin-to-glucose ratios have been used in the past to diagnose the presence of insulinoma, but their use is no longer recommended due to the high incidence of false-positive results. Fructosamine and glycosylated hemoglobin (GHb) have not been validated in ferrets yet. Other blood tests are usually unremarkable, but may indicate concurrent disease. Likewise, radiographs and ultrasound are usually unremarkable due to the small size of tumors.

Histopathology of surgical biopsy is required for definitive diagnosis. Tumors may be described as hyperplasia, adenomas, or carcinomas, and a specific tumor may have a combination of any of these processes. Immunohistochemistry has been used to further characterize pancreatic islet cell tumors and their metastasis in distant organs.

Treatment

Surgery

Surgical resection of pancreatic nodules or partial pancreatectomy is considered the treatment of choice for greater clinical resolution and longer survival times. An intravenous catheter should be placed prior to surgery, and 5% dextrose should be administered perioperatively to prevent a hypoglycemic crisis. Careful visualization with gentle palpation of the pancreas is performed to locate pancreatic nodules. These may be removed individually or, in the case of multiple nodules, a partial pancreatectomy can be performed. In one study, ferrets with partial pancreatectomy had longer survival times than those with nodulectomies. This is probably because microscopic tumors can be missed through nodulectomy alone. A full abdominal exploratory is recommended to evaluate for potential metastasis and concurrent conditions (e.g. adrenal disease). Biopsies of suspicious tissues should be collected for histologic evaluation.

The goal of surgery is to have patients normoglycemic following surgery, however some may remain hypoglycemic and many will have a recurrence of clinical signs within several months because of tumor metastasis. Case studies have demonstrated that as many as 52% of ferrets remain hypoglycemic following surgery, and reported disease-free intervals range from 0 to 23.5 months. Because of likely recurrence, owners should be advised that surgery is not curative but rather it may temporarily stop or slow the progression of disease and provide a longer disease-free interval than medical therapy alone. In one study, nodulectomy combined with partial pancreatectomy had a significantly longer median survival time (668 days), compared with nodulectomy alone (456 days) or medical treatment only (186 days).

Although some patients may need continued medical management of hypoglycemia postoperatively, clinical signs can usually be controlled on lower doses of medication than before surgery. In some patients, iatrogenic hyperglycemia may be exhibited after partial pancreatectomy, but this is usually transient and resolves within a few weeks without major treatment.

Symptomatic therapy

Palliative drug therapy does not slow or stop tumor growth, and drug dosages will need to be increased periodically as disease progresses.

Glucocorticoids increase blood glucose levels by inhibiting cellular uptake, promoting hepatic gluconeogenesis, and inhibiting insulin binding to insulin receptors. Prednisolone (Pediapred Liquid) 0.5-2 mg/kg q 12 h PO can usually control mild to moderate clinical signs. Begin at lowest dosage and gradually increase as needed to control symptoms. Blood glucose is rechecked at regular intervals and the dose is adjusted as needed to achieve normoglycemia. Although ferrets appear to be relatively resistant to the immunosuppressive effects of prednisolone, long-term administration can result in abdominal weight gain and slow regrowth of hair in shaved areas.

Diazoxide inhibits insulin secretion, and stimulates the release of epinephrine. It promotes hepatic gluconeogenesis and glycogenolysis, and decreases cellular insulin uptake. Begin diazoxide at 5-10 mg/kg q 12 h PO; dose can be increased gradually to 30 mg/kg q 12 h if lower dosages are inadequate. Diazoxide can be used as the initial palliative therapy in lieu of prednisolone, but it is considerably more expensive. If prednisolone is used initially, diazoxide is added when clinical signs cannot be controlled with prednisone alone. Often, the dosage of prednisone may be lowered once diazoxide therapy has been added.

Octreotide is a somatostatin analog that inhibits insulin secretion by the pancreatic tumor. Limited use in ferrets has been reported, but octreotide may be useful in patients that are not responding to traditional palliative therapy. Reported dosage is 1-2 μg/kg q 8-12 h SQ. Not all insulinomas are responsive to this medication.

Decreases in blood glucose in the ferret often lead to increases histamine release and stomach acid production. Famotidine 0.5 mg/kg PO q 12-24 h will help to alleviate the pain, nausea and inappetence associated with insulinoma.

Chemotherapy

Doxorubicin chemotherapy for insulinoma has direct toxic effects on pancreatic beta cells. Pre-treatment workup should include CBC, blood chemistry, ECG, and chest radiographs. The patient is pretreated with diphenhydramine 5 mg IM, and doxorubicin is infused at 30 mg/m2 (approximately 1 mg/kg) IV. The regimen is repeated q 3 weeks for 4 doses. The drug has to be infused slowly IV, and reported side-effects include bone marrow suppression, gastroenteritis, nephrotoxicity, and cardiac toxicity. The recommended cumulative dose for doxorubicin is less than 240 mg/m2.

Diet modification

Dietary changes are equally important in the management of insulinomas in ferrets. Owners should discontinue all high-sugar treats such as raisins, yogurt drops, peanut butter, or corn syrup-based supplements (i.e. Nutrical). The rapid increase in blood glucose from the ingestion of these simple sugars can induce a rebound insulin release and trigger a hypoglycemic episode. Changing the diet to a high-protein, low-carbohydrate diet is recommended, however the owner needs to be certain the ferret accepts the new diet; ferrets tend to be picky about new food items and may experience hypoglycemia from inadequate food intake. Food should be available at all times; it may need to be placed in multiple areas to ensure easy access. Offering food to ferrets (and hand feeding them, when necessary) every 4 hours, especially right before playing and after sleeping, will help to prevent hypoglycemic episodes.

Management of a hypoglycemic episode

If clinical signs are noted, the ferret should immediately be fed a high-protein, easily digestible diet (Oxbow Carnivore Care) to abate symptoms. If the ferret presents comatose or exhibiting seizures, corn syrup or sugar solution can be applied to the oral mucous membranes to provide temporary relief. Blood glucose level should be quickly assessed for hypoglycemia, and an intravenous catheter should be placed immediately for a slow bolus of 50% dextrose (0.25-2 mL), titrated to effect. Once seizures have ceased, the patient should be placed on maintenance fluids with 5% dextrose. If the ferret continues to seizure despite IV glucose, diazepam (1 mg/kg IV) may be required to stop the seizures.

Prevention

Ferrets are obligate carnivores. The typical ferret diet in the US contains 22-42% protein, 15-28% fat, 10-45% carbohydrate, and 1.5-3.5% fiber. Such high levels of carbohydrate are unnatural and may have negative consequences for the ferret. Finkler advocates a nutritional approach to insulinoma prevention, and recommends a diet low in carbohydrates, and high in fat and protein. Simple sugars should be completely avoided. He recommends a diet containing 42-55% protein, 18-30% fat, only 8-15% carbohydrates, and 1-3% fiber.

Wild polecats consume whole, small prey such as rodents, lagomorphs, and birds. Their natural diet is high in proteins and fat and low in carbohydrates and fiber. A growing number of experts are recommending that ferrets be fed a diet that more closely mimics natural diet: raw meat and bone. Some advocate the feeding of prey items such as mice and chicks. The nutrient analysis of a rat carcass, for example, is 55% protein, 38.1% fat, 1.2% carbohydrate, and 0.55% fiber. Commercially available archetypal diets that have been designed to mimic the nutrient profile of whole prey include Ferret Archetypal (Wysong), Natural Gold (Pretty Pets), and Evo Ferret Diet (Innova).

Beta cell tumors in the ferret may be prevented by switching to an ancestral diet that is high in protein and fat, and low in carbohydrate and fiber; however, studies supporting this theory are currently lacking and further scientific investigations are warranted before specific recommendations can be made.

References

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